Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.

BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.

Interaction of Clostridioides difficile infection with frailty and cognition in the elderly: a narrative review.

PURPOSE: Clostridioides difficile infection (CDI) is the leading cause of antibiotic-related diarrhea and healthcare-associated infections, affecting in particular elderly patients and their global health. This review updates the understanding of this infection, with focus on cognitive impairment and frailty as both risk factors and consequence of CDI, summarizing recent knowledge and potential mechanisms to this interplay. METHODS: A literature search was conducted including terms that would incorporate cognitive and functional impairment, aging, quality of life, morbidity and mortality with CDI, microbiome and the gut-brain axis. RESULTS: Advanced age remains a critical risk for severe disease, recurrence, and mortality in CDI. Observational and quality of life studies show evidence of functional loss in older people after acute CDI. In turn, frailty and cognitive impairment are independent predictors of death following CDI. CDI has long-term impact in the elderly, leading to increased risk of readmissions and mortality even months after the acute event. Immune senescence and the aging microbiota are key in susceptibility to CDI, with factors including inflammation and exposure to luminal microbial products playing a role in the gut-brain axis. CONCLUSIONS: Frailty and poor health status are risk factors for CDI in the elderly. CDI affects quality of life, cognition and functionality, contributing to a decline in patient health over time and leading to early and late mortality. Narrative synthesis of the evidence suggests a framework for viewing the cycle of functional and cognitive decline in the elderly with CDI, impacting the gut-brain and gut-muscle axes.

Ethambutol-induced bullous skin lesions in mycobacterium kansasii lung infection.

Mycobacterium kansasii is the second most common cause of nontuberculous mycobacterial (NTM) lung disease after Mycobacterium avium complex infection in the United States.[1] The first-line therapy for M. kansasii is a three-drug regimen including rifampin, isoniazid, and ethambutol. We present a case of a patient with pulmonary M. kansasii who developed bullous skin lesions while receiving this regimen and again after rechallenge with ethambutol. In patients with intolerance to one of the first-line antibiotics, a multidisciplinary team approach to starting second-line agents is needed. Ethambutol should be included in the differential diagnosis of drug-induced bullous skin lesions in treated patients with NTM, who develop new onset rash with blisters or ulceration.

Women Physicians: Gender and the Medical Workplace.

Background: Understanding the work habits, attitudes, and experiences of women physicians is critical for optimal patient care. In a gendered work environment, obstacles faced hinder women physicians from contributing to their full ability. This study investigated how women physicians' work habits are viewed, in the context of women's attitudes and experiences. Methods: An analysis of the medical literature (1990-2017) was undertaken. Published studies were located using search engines, article references, consultation with experts, and relevant Mesh terms. Of 1185 listings, 354 studies were evaluated and 44 articles, selected by three reviewers, were analyzed in detail. Results: Four themes emerged-practice styles, productivity, prevailing attitudes, and the workplace environment. Comparing women physicians to male colleagues as a standard for evaluating performance, for example, undervalues distinctive characteristics women bring to medical practice. Productivity models that focus on work hours, procedures, and publications do not encompass the full scope of patient care. Conclusions: Solutions offered mainly have been designed to help women physicians fit into existing workplace environments, but traditionally available "adapt or exit" options in response to challenges faced appear insufficient. A gender equity perspective helps to explain findings and suggests ways to reshape the health care workplace to better understand, utilize, and retain women physicians.

Tongue discoloration in an elderly kidney transplant recipient: Treatment-related adverse event?

BACKGROUND: With the increased occurrence of methicillin-resistant staphylococcus aureus infections, linezolid treatment might be administered more often. New rare adverse events are likely to follow. CASE SUMMARY: A 65-year-old man (weight, 91 kg; height, 185 cm) presented to the emergency department at the University of Virginia-affiliated Salem Veterans Affairs Medical Center, Salem, Virginia, after a recent (8 weeks) kidney transplantation with a 24-hour history of fatigue, chills, arthralgias, increased urinary frequency, and onset of tongue discoloration. Two days before admission, he completed a 14-day course of linezolid 600 mg PO BID for ampicillin-resistant enterococcal urinary tract infection. He was afebrile on admission and the dorsal aspect of his tongue was blackened centrally, browner peripherally, with normal pink mucosa on the periphery. Based on the Naranjo probability scale, the calculated score for tongue discoloration as a drug-related adverse event was 7 out of a maximum score of 13 points, designating it as a probable cause. The patient's tongue discoloration improved moderately during the hospital stay and resolved 6 months after the discontinuation of linezolid. CONCLUSIONS: We report a rare association of linezolid and tongue discoloration in an elderly kidney transplant recipient that improved with discontinuation. We present this case to increase clinicians' awareness of the potential adverse event.

Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza.

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrollment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.

Management of infections in palliative care patients with advanced cancer.

To characterize infections and their management in oncology patients at the end of life, we conducted a review of the literature. Eight studies assessing infection in 957 patients with various malignancies were identified. Forty-two percent of terminally ill patients developed infections in the final phase of care. The greatest frequency of treatment with antibiotics occurred in acute care hospitals. Enterobacteriaceae and S. aureus were the most frequently isolated bacteria, and urinary and respiratory tracts the most frequently involved sites of infection. A total of 19-39% of individuals with suspected infection and advanced cancer died. The decision whether to treat or not in the palliative care setting may be complex and requires an individualized approach. Further research in this area will help develop a consensus for management that will facilitate education of students and residents regarding complex decisions of care of infections at the end of life.