Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein.

BACKGROUND: Patients with antibody deficiency respond poorly to coronavirus disease 2019 (COVID-19) vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesized that immunoglobulin preparations will now contain neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies, which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralizing capacity of patient samples and immunoglobulin products was assessed using in vitro pseudovirus and live-virus neutralization assays, the latter investigating multiple batches against current circulating Omicron variants. We describe the clinical course of 9 patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titer increased from 2123 to 10 600 U/mL postinfusion, with corresponding increase in pseudovirus neutralization titers to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralization, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum >900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralizing anti-SARS-CoV-2 antibodies that are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity.

New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.

CD6 attenuates early and late signaling events, setting thresholds for T-cell activation.

The T lineage glycoprotein CD6 is generally considered to be a costimulator of T-cell activation. Here, we demonstrate that CD6 significantly reduces early and late T-cell responses upon superantigen stimulation or TCR triggering by Abs. Measuring calcium mobilization in single cells responding to superantigen, we found that human T cells expressing rat CD6 react significantly less well compared with T cells not expressing the exogenous receptor. When the cytoplasmic domain of rat CD6 was removed, calcium responses were recovered, indicating that the inhibitory properties of CD6 are attributable to its cytoplasmic domain. Calcium responses, and also late indicators of T-cell activation such as IL-2 release, were also diminished in TCR-activated Jurkat cells expressing human CD6, compared with CD6-deficient cells or cells expressing a cytoplasmic deletion mutant of human CD6. Similarly, calcium signals triggered by anti-CD3 were enhanced in human T lymphocytes following morpholino-mediated suppression of CD6 expression. Finally, the proliferation of T lymphocytes was increased when the CD6-CD166 interaction was blocked with anti-CD166 Abs, but inhibited when anti-CD6 Abs were used. Our data suggest that CD6 is a signaling attenuator whose expression alone, i.e. in the absence of ligand engagement, is sufficient to restrain signaling in T cells.

Clinical Reasoning: Progressive Hemiparesis and White Matter Abnormalities in an HIV-Negative Patient.

A 61-year-old man from India was admitted to hospital after being found unresponsive by the roadside. He was treated with dual-antiplatelet therapy for an acute coronary syndrome. Ten days into admission, he had mild left-sided face, arm, and leg weakness, which progressed significantly over the next 2 months in association with progressive white matter abnormalities on brain MRI. In this case study, we outline our clinical reasoning, which led to the detection of a rare underlying cause of a devastating neurologic disease. We also present our approach to treatment, which achieved a sustained clinical and radiologic response.

Thoracic empyema: current opinions in medical and surgical management.

PURPOSE OF REVIEW: Empyema is defined as pus in the thoracic cavity due to pleural space infection and has a multifactorial underlying cause, although a majority of them are post-bacterial pneumonia caused by tuberculosis or by infection following penetrating chest injuries or surgical procedures. It is still associated with significant morbidity and mortality in adults and children despite optimal management according to current guidelines. Historically, empyema management has been empirical, but more recent data are leading to more focused management guidelines. RECENT FINDINGS: The number of therapeutic agents licensed for intrapleural use or undergoing clinical trials in the management of empyema continues to expand, although their use is currently controversial and probably best limited to trials and specialist centers. Although their use is limited by availability, ultrasound and guided aspiration is the investigation of choice in suspected empyema. It is safer, more sensitive, provides more information, and, in the case of guided-drainage, is more likely to be effective. Finally, there is a growing body of literature that supports very early involvement of thoracic surgeons in empyema management. An emerging question for the future is whether some or indeed all patients with empyema should now bypass medical thoracostomy and proceed directly to video-assisted thoracoscopic surgery for both acute and chronic empyemas. SUMMARY: A summary of the most recent opinions and results in thoracic empyema management is outlined. Treatment of empyema can be summarized as appropriate antibiotic therapy combined with medical or surgical pleural space drainage, management of any underlying factors, with further surgery indicated for chronic disease.

Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.

BACKGROUND: Empyema is an increasingly frequent clinical problem worldwide, and has substantial morbidity and mortality. Our objectives were to identify the clinical, surgical and microbiological features, and management outcomes, of empyema. METHODS: A retrospective observational study over 12 years (1999-2010) was carried out at The Heart Hospital, London, United Kingdom. Patients with empyema were identified by screening the hospital electronic 'Clinical Data Repository'. Demographics, clinical and microbiological characteristics, underlying risk factors, peri-operative blood tests, treatment and outcomes were identified. Univariable and multivariable statistical analyses were performed. RESULTS: Patients (n = 406) were predominantly male (74.1%); median age = 53 years (IQR = 37-69). Most empyema were community-acquired (87.4%) and right-sided (57.4%). Microbiological diagnosis was obtained in 229 (56.4%) patients, and included streptococci (16.3%), staphylococci (15.5%), gram-negative organisms (8.9%), anaerobes (5.7%), pseudomonads (4.4%) and mycobacteria (9.1%); 8.4% were polymicrobial. Most (68%) cases were managed by open thoracotomy and decortication. Video-assisted thoracoscopic surgery (VATS) reduced hospitalisation from 10 to seven days (P = 0.0005). All-cause complication rate was 25.1%, and 28 day mortality 5.7%. Predictors of early mortality included: older age (P = 0.006), major co-morbidity (P = 0.01), malnutrition (P = 0.001), elevated red cell distribution width (RDW, P<0.001) and serum alkaline phosphatase (P = 0.004), and reduced serum albumin (P = 0.01) and haemoglobin (P = 0.04). CONCLUSIONS: Empyema remains an important cause of morbidity and hospital admissions. Microbiological diagnosis was only achieved in just over 50% of cases, and tuberculosis is a notable causative organism. Treatment of empyema with VATS may reduce duration of hospital stay. Raised RDW appears to associate with early mortality.

Wound management and restrictive arm movement following cardiac device implantation - evidence for practice?

BACKGROUND: The rate of cardiac device implantation has risen significantly secondary to an increase in the number of indications. Wound infection and lead displacement are two common and potentially life-threatening complications. No national/international guidelines address postoperative care and controversy exists regarding wound management and arm movement following cardiac device implantation. AIMS: We aimed to explore and review the evidence behind current practice but found that certain aspects of established practice. METHODS: An electronic search of the databases EMBASE, British Nursing Index, CINAHL, Cochrane and PubMed to identify evidence regarding wound management and lead displacement. FINDINGS: We found that certain aspects of established practice are based on tradition rather than evidence. Recent guidelines on wound management published by The National Institute for Health and Clinical Excellence in the UK recommend covering the wound postoperatively for 48 h with a low-adherent transparent dressing and letting patients shower thereafter. Since specific guidelines for cardiac device patients are lacking, we suggest that further research address whether or not the NICE guidelines can be extrapolated to this area. Studies showed that early mobilisation and allowing a full range of arm movements following device implantation is safe. Further research must validate these findings. CONCLUSION: We discuss the reasons behind these gaps in the evidence base and support the idea that nursing education has not placed enough emphasis on how to critically appraise research. This accounts for the very small proportion of nurses that get involved in conducting research and generating guidelines. Additionally, we argue that nurses can play a key role in identifying and addressing research questions that lead to improved patient outcome. Thus, we support proposals to enhance nurses' opportunities to pursue academic careers to achieve adequate research skills.