Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Cutaneous lupus-erythematosus-like reaction arising after COVID-19 vaccination.

Multiple adverse cutaneous reactions have been described following vaccination against COVID-19. This case report describes a reaction to the Pfizer-BioNTech (BNT162b2) vaccine that histopathologically resembles cutaneous lupus erythematosus with vacuolar interface alteration, superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrate with clusters of CD123+ cells, and mildly increased dermal mucin.

Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety.

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a six-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C-reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.

Cytomegalovirus Humoral Response Against Epithelial Cell Entry-Mediated Infection in the Primary Infection Setting After Hematopoietic Cell Transplantation.

BACKGROUND: The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood. METHODS: To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR). RESULTS: There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm). CONCLUSIONS: This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients.

Clinical Features and Outcomes of 105 Hospitalized Patients With COVID-19 in Seattle, Washington.

BACKGROUND: Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management. METHODS: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death. RESULTS: One hundred five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years, and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%), and diabetes (33%) being the most prevalent. Most (63%) had symptoms for ≥5 days prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation, and the overall mortality rate was 33%. CONCLUSIONS: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.

Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy.

Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 (P = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 107 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

A Co-Located Continuity Clinic Model to Address Healthcare Needs of Women Living Unhoused With Opioid Use Disorder, Who Engage in Transactional Sex in North Seattle.

This is a review of the first 50 patients attending a colocated continuity clinic with harm reduction services to women experiencing homelessness in north Seattle. Among those tested, patients had high rates of curable sexually transmitted infections (44%), injection opioid use (36%), transactional sex (69%), unintended pregnancy (10%), and human immunodeficiency virus infections (10%).

Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis.

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.

Cytomegalovirus shedding from breastmilk and mucosal sites in healthy postpartum women: A pilot study.

Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by polymerase chain reaction in breastmilk, vaginal, and saliva samples from nine healthy CMV-seropositive postpartum women for 28 days. CMV was found in seven of nine women and 171 of 253 breastmilk samples (67.6%). In four women, all breastmilk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral, and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted.

Washington state satellite HIV clinic program: a model for delivering highly effective decentralized care in under-resourced communities.

To improve access to high-quality HIV care in underserved regions of Western Washington (WA) State, we collaborated with the WA State Department of Health (DOH) and community partners to launch four satellite HIV clinics. Here, we describe this innovative clinical care model, present an estimate of costs, and evaluate patient care outcomes, including virologic suppression rates. To accomplish this, we assessed virologic suppression rates 12 months before and 12 months after the satellite clinics opened, comparing people living with HIV (PLWH) who enrolled in the satellite clinics versus all PLWH in the same regions who did not. We also determined virologic suppression rates in 2015 comparing satellite clinic versus non-satellite clinic patients and compared care quality indicators between the satellite clinics and the parent academic clinic. Results demonstrate that the change in virologic suppression rate 12 months before to 12 months after the satellite clinics opened was higher for patients who enrolled in the satellite clinics compared to all those in the same region who did not (18% versus 6%, p < 0.001). Virologic suppression in 2015 was significantly higher for satellite clinic than non-satellite clinic patients at three of four sites. Care quality indicators were met at a high level at the satellite clinics, comparable to the parent academic clinic. Overall, through community partnerships and WA DOH support, the satellite clinic program increased access to best practice HIV care and improved virologic suppression rates in difficult-to-reach areas. This model could be expanded to other regions with inadequate access to HIV practitioners, though financial support is necessary.

CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.

The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.

A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia.

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1-5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m(2) dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m(2) of belinostat plus 75 mg/m(2) of AZA on days 1-5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.

Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial.

We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival.

Patient Preferences Comparing Linear Versus Purse String Closures in Dermatologic Surgery Utilizing a Novel Simulator-Based Educational Tool.

BACKGROUND: Patients often query in regard to cosmetic outcomes after cutaneous surgery. This study provides information on this topic by surveying preference on 2 skin closure methods, purse and linear. The authors used a novel method to poll opinions by incorporating simulated skin within the context of the survey. OBJECTIVE: To determine patient's preference for linear or purse string closure. Additional outcomes were to survey patient's opinions regarding which scar characteristics have the highest cosmetic impact, the cosmetic importance of a scar, and the utility of simulators, and patient photographs as methods of understanding closure techniques. MATERIALS AND METHODS: Participants were prospectively recruited to complete a survey. Data outcomes were analyzed using descriptive statistics and the chi-square test of association. RESULTS: About half of the participants (54.7%) preferred linear closure. Preference was independent of gender (p = .90) or having a prior linear or purse string closure (p = .17). Patient photographs were the most influential for determining preference according to 86.2% of participants; however, 88% of the participants found simulator devices useful for educational purposes. CONCLUSION: The methods in this survey may represent a venue for educating patients and incorporating their preferences into the choices they will make regarding dermatologic procedures, which they will undergo.

Microcystic adnexal carcinoma in the axilla of an 18-year-old woman.

Microcystic adnexal carcinoma (MAC) is an uncommon adnexal neoplasm with a predilection for the head and neck. The tumor rarely metastasizes but is locally aggressive and commonly demonstrates perineural invasion. MAC occurs most often in older adults. This report describes a young woman with a MAC in her left axilla who required two stages of Mohs micrographic surgery followed by a wide local excision because of persistent perineural invasion in close proximity to the brachial plexus. Other cases presenting in the pediatric age group are discussed.

Myxoid stroma and delicate vasculature of a superficial angiomyxoma give rise to the red planet sign.

Superficial angiomyxomas are uncommon benign mesenchymal tumors. They often recur locally if partially removed. This case report demonstrates not only the characteristic pathological findings of a superficial angiomyxoma in a 33- year-old man, but also shows a unique dermatoscopic image, which in our estimation resembles a celestial red planet such as the blood moon seen during a lunar eclipse. We propose to call this the "red planet" sign for a superficial angiomyxoma on dermoscopic examination.

Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation: Significance of Novel Transplantation Techniques.

Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 187 episodes of late CMV disease among 2469 day 100 survivors and the estimated cumulative incidence of first late CMV disease was 6.7% (95% CI 5.6-%-7.6%) with no difference between the PET 6.7% (95% CI 5.7%-7.8%) and the letermovir group 5.4% (95% CI 3.2%-8.3%). 32 (1.3%) patients had a second episode of late CMV disease. In multivariable Cox regression models, post-transplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia detected before day 100, corticosteroid treatment after day 100 at dose ≥1mg/kg, acute and chronic GvHD, lymphopenia, HLA mismatched related donors status and recipient age were also associated with late CMV disease. HLA mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by year two after HCT. In summary, late CMV disease continues to occur in the current era. Improved prevention strategies for late CMV disease are needed.

CMV Reactivation during Pre-Transplantation Evaluation: A Novel Risk Factor for Post-Transplantation CMV Reactivation.

Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-17) and letermovir prophylaxis (2018-21) eras. CMV DNA PCR surveillance was routinely performed during the pre-HCT work-up period, and antiviral therapy was recommended according to risk for progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified and 11% had pre-HCT CMV reactivation 14 days (median; IQR 6-23 days) before HCT. Lymphopenia (≤300 cells/uL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year post-HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV endpoints were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates and antiviral therapy may be indicated to prevent post-HCT CMV reactivation.