There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people ...worldwide
. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care
. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines
that may be produced by a subset of inflammatory monocytes
, lymphopenia
and T cell exhaustion
. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
We conducted a randomized, open-label, phase 3 ...trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).
Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We ...retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.
This review describes the incidence, epidemiology, and risk factors for mortality of COVID-19 in immunocompromised patients, including persons with human immunodeficiency virus. It describes various ...preventive measures, including vaccines and their effectiveness and the role of monoclonal antibodies for pre-exposure prophylaxis. It also reviews the different treatment options for immunocompromised individuals, including antivirals, monoclonal antibodies, and immunomodulators. Lastly, it describes the impact of COVID-19 on transplantation and continuity care of this population.
Infective endocarditis remains an uncommon disease with significant morbidity and mortality. In the last two decades, progress has been made describing the unique aspects of infective endocarditis in ...solid organ transplant (SOT) recipients.
Incidence of infective endocarditis in SOT is higher when compared with the general population. End-stage organ dysfunction, diabetes mellitus, older age, and prior intravenous lines have been identified as risk factors predisposing to infective endocarditis in SOT. Staphylococci and enterococci represent the most frequently isolated pathogens, whereas fungi are rarely isolated. Median time from transplantation to diagnosis ranges from 33 to 66 months. Nosocomial acquisition and mural endocarditis are more common in SOT recipients with infective endocarditis. Procurement of organs from patients with infective endocarditis might be well tolerated so long as close monitoring and targeted antibiotics are given. Selected patients might benefit from heart transplantation as definitive or salvage therapy for infective endocarditis. Outcomes of infective endocarditis in SOT recipients compared with the general population might be similar; however, patient survival and graft function are reduced when recipients suffer from infective endocarditis.
Infective endocarditis although rare can affect donors and recipients involved in the SOT process. Recognition of the unique characteristics in the presentation, prevention, medical, and surgical therapy of this disease is essential in order to minimize adverse outcomes.
Solid organ transplant recipients are at an increased risk of tuberculosis and transplant candidates should be screened early in their evaluation with a detailed history, tuberculin skin test or ...tuberculosis interferon-gamma release assay, and chest radiograph. For latent tuberculosis treatment, isoniazid and rifamycin-based regimens have advantages and disadvantages; treatment decisions should be customized. Tuberculosis after solid organ transplantation generally occurs after months or years; early infections should raise the possibility of donor-derived infections. Tuberculosis diagnosis and treatment in solid organ transplant recipients may be complicated by protean manifestations, drug interactions, and adverse drug reactions.
Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or ...side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.
Tuberculosis (TB) infection in solid organ transplant recipients poses unique diagnostic and treatment challenges. Recent guidelines for prevention of donor-derived TB and updates on TB diagnostics ...and treatment in the transplant setting are reviewed as follows.
Prevention of donor-derived TB can be optimized by careful screening of donors with risk factors for TB, with effort taken to rule out active TB in the donor, and targeted treatment of recipients. However, transmission may still occur, especially through lung allografts, given limitations of screening tests and treatment strategies. Diagnostics for latent tuberculosis infection are limited in sensitivity and have a relatively low predictive value for development of active TB. Treatment options for latent and active TB carry risks that are still being elucidated in transplant patients, such as a dysregulated inflammatory response manifested by immune reconstitution syndrome.
More sensitive diagnostics in deceased donors are needed to quantify the risk of TB transmission and the risk of progression to active tuberculosis in those with latent tuberculosis infection prior to transplant. Novel TB therapies of shorter duration with less toxicity for both latent and active TB will be of great benefit to transplant patients.
infection (CDI) is a health care-associated infection associated with significant morbidity and cost, with highly varied risk across populations. More effective, risk-based prevention strategies are ...needed. Here, we investigate risk factors for hospital-associated CDI in a large integrated health system. In a retrospective cohort of all adult admissions to 21 Intermountain Healthcare hospitals from 2006 to 2012, we identified all symptomatic (i) hospital-onset and (ii) health care-facility-associated, community-onset CDI. We then evaluated the risk associated with antibiotic exposure, including that of specific agents, using multivariable logistic regression. A total of 2,356 cases of CDI among 506,068 admissions were identified (incidence, 46.6 per 10,000). Prior antibiotic use was the dominant risk factor, where for every antibiotic day of therapy prior to the index admission, the odds of subsequent CDI increased by 12.8% (95% confidence interval CI, 12.2 to 13.4%;
< 0.0001). This was a much stronger association than was inpatient antibiotic exposure (odds ratio OR, 1.007 95% CI, 1.005 to 1.009;
< 0.0001). The highest-risk antibiotics included second-generation and later cephalosporins (especially oral), carbapenems, fluoroquinolones, and clindamycin, while doxycycline and daptomycin were associated with a lower CDI risk. We concluded that cumulative antibiotic exposure prior to admission is the greatest contributor to the risk of subsequent CDI. Most classes of antibiotics carry some risk, which varies by drug and route. This information may be useful for antimicrobial stewardship efforts.
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