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The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients. Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.

The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

Introduction Allergic bronchopulmonary aspergillosis (ABPA) affects millions worldwide, yet current treatment approaches remain suboptimal due to a one-size-fits-all model that fails to account for the significant heterogeneity across affected populations. While corticosteroids and itraconazole are commonly prescribed, there are associated risks and uncertainties regarding efficacy. Additionally, the efficacy of alternatives such as newer and higher activity triazole antifungals, or the place of “biologic” therapies like anti-IL5 antagonists, has not been thoroughly investigated. Objectives This review will assess treatment outcomes in patients with ABPA (Population) receiving antifungal or biologic therapies (Intervention) compared with corticosteroids, placebo, or alternative active treatments (Comparator), evaluating lung function (FEV₁), serological markers, exacerbation frequency, patient-reported outcomes, steroid-sparing effects, and adverse events (Outcomes) through a systematic review and network meta-analysis of published peer-reviewed studies. Inclusion criteria All articles using the Population, Exposure/Intervention, Comparator, Outcomes, Duration, and Results (PECODR) framework related to human patients published in English from inception to the date of undertaking the study (present) will be included. Materials and methods The following literature databases will be searched: MEDLINE, EMBASE, Cochrane Library Trials database, PubMed Central, Web of Science, and Scopus from inception to the present in collaboration with an experienced librarian. The primary researcher will screen the titles and abstracts; deduplication will be performed using Covidence®, and inclusion will be validated by a second checker. Quantitative analyses will be performed to summarise the results as means, frequency tables, and odds ratios of outcomes. Where there is sufficient data, a network meta-analysis will be conducted. The systematic review and network meta-analysis will be undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) framework. Systematic review registration PROSPERO CRD42024443073.

Streptococcus pneumoniae is the second commonest cause of bacterial mortality worldwide. Interactions of S pneumoniae with alveolar macrophages are important for the protective inflammatory responses during early lung infection. Pneumolysin is a well-recognised virulence factor for S pneumonia; the toxin has multiple effects on the host immune response that are primarily thought to be proinflammatory. Our aim was to characterise the inflammatory effects of pneumolysin on macrophages. We used in-vitro culture of primary human monocyte-derived macrophages (MDM) with S pneumoniae and an isogenic mutant lacking pneumolysin. We measured cytokine production (including tumour necrosis factor [TNF] and interleukin 6 [IL6]) at transcriptional and protein level, as well as transcription factor function, to look at mechanisms of interaction between MDM and bacteria. We extended these data with epithelial cell line work and neutrophil transmigration models. Then we used a murine intranasal infection model to assess functional effects in vivo. Higher mean concentrations of TNF and IL6 were induced from MDM in response to pneumolysin-deficient bacteria than in response to wild-type bacteria (6014 pg/ml [SD 970] vs 2295 [470] and 821 [374] vs 89 [28], respectively). This finding was reflected in TNF mRNA (change in cycle threshold 4·3 vs 2·4) and IL6 mRNA (3·5 vs 0·4). Transcriptome analysis of MDMs after S pneumoniae infection confirmed increased expression of a range of proinflammatory genes, including IL12, IL27, CCR7, IL5, and CCL5, in response to the pneumolysin mutant. The increase in transcription of proinflammatory genes and concentrations of TNF and IL6 in supernatant in response to the pneumolysin-deficient strain were abrogated by inhibition of phagocytosis. In a murine pneumonia model, despite more rapid clearance of the pneumolysin-deficient mutant (1 × 104 colony-forming units [CFU]/mL) compared with the wild type strain (1 × 105 CFU/mL) from bronchoalveolar lavage fluid (BALF) by 4 h, mean concentrations of TNF were elevated in BALF fluid with the mutant (1336 pg/mL [SD 130] vs 6164 [632]). This increase was associated with more rapid neutrophil influx with the pneumolysin-deficient mutant than with the wild-type strain into BALF seen at 2 h (107 neutrophils per mL [SD 39] vs 3303 [1624]). Blockade of TNF abrogated the differences in clearance between the pneumolysin mutant and wild-type strain. These data indicate an unexpected role for pneumolysin as an initial suppressor of macrophage inflammatory responses, which is dependent on phagocytosis. The early inflammation dampening effects of pneumolysin released within the phagolysosome might be an important contribution to the virulence of S pneumoniae. The inhibition of TNF release allows increased bacterial replication early during the course of infection, and presumably is an evolutionary advantage. Medical Research Council.

Quorum sensing regulates bacterial social behaviors by production, secretion, and sensing of pheromones. In this study, we characterized a new quorum-sensing system of the Rgg/SHP class in S. pneumoniae D39. The system was found to directly induce the expression of a single gene cluster comprising the gene for the SHP pheromone and genes with putative functions in capsule synthesis. Capsule size, as measured by dextran exclusion, was increased by SHP exposure in R36A, an unencapsulated derivative of D39. In the encapsulated parent strain, overexpression of the gene cluster increased capsule size, supporting the role of Rgg/SHP in the synthesis of surface polysaccharides. Further, we found that biofilm formation on epithelial cells was reduced by overexpression of the system and increased in a mutant with an rgg deletion. Placing surface polysaccharide expression under quorum-sensing regulation may enable S. pneumoniae to tune interactions with the host and other bacteria in accordance with environmental and cell density conditions. Despite vaccines, Streptococcus pneumoniae kills more than a million people yearly. Thus, understanding how pneumococci transition from commensals to pathogens is particularly relevant. Quorum sensing regulates collective behaviors and thus represents a potential driver of commensal-to-pathogen transitions. Rgg/small hydrophobic peptide (SHP) quorum-sensing systems are widespread in streptococci, yet they remain largely uncharacterized in S. pneumoniae . Using directional transcriptome sequencing, we show that the S. pneumoniae D39 Rgg0939/SHP system induces the transcription of a single gene cluster including shp and capsule gene homologs. Capsule size measurements determined by fluorescein isothiocyanate-dextran exclusion allowed assignment of the system to the regulation of surface polysaccharide expression. We found that the SHP pheromone induced exopolysaccharide expression in R36A, an unencapsulated derivative of D39. In the encapsulated parent strain, overexpression of the Rgg system resulted in a mutant with increased capsule size. In line with previous studies showing that capsule expression is inversely associated with biofilm formation, we found that biofilm formed on lung epithelial cells was decreased in the overexpression strain and increased in an rgg deletion mutant. Although no significant differences were observed between D39 and the rgg deletion mutant in a mouse model of lung infection, in competitive assays, overexpression reduced fitness. This is the first study to reveal a quorum-sensing system in streptococci that regulates exopolysaccharide synthesis from a site distinct from the original capsule locus. IMPORTANCE Quorum sensing regulates bacterial social behaviors by production, secretion, and sensing of pheromones. In this study, we characterized a new quorum-sensing system of the Rgg/SHP class in S. pneumoniae D39. The system was found to directly induce the expression of a single gene cluster comprising the gene for the SHP pheromone and genes with putative functions in capsule synthesis. Capsule size, as measured by dextran exclusion, was increased by SHP exposure in R36A, an unencapsulated derivative of D39. In the encapsulated parent strain, overexpression of the gene cluster increased capsule size, supporting the role of Rgg/SHP in the synthesis of surface polysaccharides. Further, we found that biofilm formation on epithelial cells was reduced by overexpression of the system and increased in a mutant with an rgg deletion. Placing surface polysaccharide expression under quorum-sensing regulation may enable S. pneumoniae to tune interactions with the host and other bacteria in accordance with environmental and cell density conditions.

Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae , but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis. Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae . The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that this would reduce activation of host innate inflammatory responses by preventing activation of intracellular proinflammatory signaling pathways. We investigated this hypothesis in human monocyte-derived macrophages stimulated with encapsulated or isogenic unencapsulated mutant S. pneumoniae . Unexpectedly, despite strongly inhibiting bacterial internalization, the capsule resulted in enhanced inflammatory cytokine production by macrophages infected with S. pneumoniae . Experiments using purified capsule material and a Streptococcus mitis mutant expressing an S. pneumoniae serotype 4 capsule indicated these differences required whole bacteria and were not due to proinflammatory effects of the capsule itself. Transcriptional profiling demonstrated relatively few differences in macrophage gene expression profiles between infections with encapsulated S. pneumoniae and those with unencapsulated S. pneumoniae , largely limited to reduced expression of proinflammatory genes in response to unencapsulated bacteria, predicted to be due to reduced activation of the NF-κB family of transcription factors. Blocking S. pneumoniae internalization using cytochalasin D had minimal effects on the inflammatory response to S. pneumoniae . Experiments using murine macrophages indicated that the affected genes were dependent on Toll-like receptor 2 (TLR2) activation, although not through direct stimulation of TLR2 by capsule polysaccharide. Our data demonstrate that the early macrophage proinflammatory response to S. pneumoniae is mainly dependent on extracellular bacteria and reveal an unexpected proinflammatory effect of encapsulated S. pneumoniae that could contribute to disease pathogenesis. IMPORTANCE Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae , but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis.

Fungal infections are increasingly prevalent; however, antifungal stewardship attracts little funding or attention. Previous studies have shown that knowledge of guidelines and scientific evidence regarding antifungals is poor, leading to prescribing based on personal experiences and the inherent biases this entails. We carried out a retrospective study of inpatient antifungal usage at two major hospitals. We assessed the longitudinal trends in antifungal usage and the effect of COVID-19 on antifungal prescription, alongside levels of empirical and diagnostically targeted antifungal usage. Our results showed that the longitudinal patterns of total systemic antifungal usage within the trusts were similar to national prescribing trends; however, the composition of antifungals varied considerably, even when looking exclusively at the more homogenous group of COVID-19 patients. We showed a high level of empirical antifungal use in COVID-19 patients, with neither trust adhering to international recommendations and instead appearing to follow prior prescribing habits. This study highlights the significant challenges to optimise antifungal use with prescribing behaviour largely dictated by habit, a lack of adherence to guidelines, and high rates of empirical non-diagnostic-based prescribing. Further research and resources are required to understand the impact of antifungal stewardship on improving antifungal prescribing behaviours in this setting and the effects on outcome.

The patient was switched to oral edoxaban after 5 days of treatment dose enoxaparin and was discharged off oxygen 5 days after presentation. Since this early case of COVID-19 in the UK, in our practice, based in London, we have observed numerous PE events in patients with COVID-19 infection. Table 1 Summary of 10 cases of COVID-19 pneumonia with pulmonary embolism identified on CT angiography Case Age Sex Presenting history Chest radiograph Relevant comorbid conditions D-dimer (ng/mL) Troponin (ng/L) Indication for CTPA HIghest level of PE on CTPA Right heart strain on CT CT evidence of infarcts Management of VTE Ventilatory support Evidence of DVT on USS A 56 Male 7 days cough, fever Bilateral infiltrates T2DM >8000 8 Chest pain Subsegmental No No DOAC High flow oxygen No B 64 Male 9 days cough, SOB Bilateral infiltrates HTN, CKD >8000 – Syncopal episode Main Yes Yes LMWH High flow oxygen No C 57 Female 15 days fever, cough SOB Clear – >8000 309 >3 weeks of SOB Main Yes Yes Thrombolysis High flow oxygen No D 71 Male 7 days lethargy, fever, cough Bilateral infiltrates – >8000 406 Persistent high P/F ratio Lobar Yes Yes LMWH High flow oxygen No E 66 Male 9 days cough, fever, SOB Right upper lobe and left lower zone consolidation – 4990 13 Persistent high P/F ratio Segmental Yes No LMWH High flow oxygen Yes F 62 Male 10 days SOB, diarrhoea Bilateral infiltrates – >8000 37 Chest pain Segmental Yes No LMWH Intubated and Ventilated No G 53 Male 13 days cough, fever, SOB Bilateral consolidative change – 2560 7 Pleuritic chest pain. Persistent high P/F ratio Lobar Yes Yes DOAC High flow oxygen No H 71 Male 13 days fever, coryza Unilateral linear atelectasis T2DM 2490 177 Syncopal episode Main Yes No LMWH High flow oxygen No I 63 Male 7 days SOB, cough, fever Bilateral infiltrates T2DM, HTN, IHD >8000 21 Clinical evidence of DVT, raised D-dimer Main Yes No LMWH High flow oxygen Yes J 75 Female Inpatient - 2 days of SOB and increasing oxygen requirement Bilateral infiltrates Bladder cancer with ureteric obstruction, COPD >8000 74 Staging CT scan Subsegmental No No Heparin infusion High flow oxygen Yes DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; HTN, hypertension; IHD, ischaemic heart disease; LMWH, low-molecular-weight heparin; P/F ratio, ratio of arterial oxygen partial pressure to fractional inspired oxygen; SOB, shortness of breath; T2DM, type 2 diabetes; USS, ultrasound. D-dimer levels are measured for prognostication, but due to the limited specificity of the assay, it is easy to overlook concomitant VTE in this patient group. [...]large prospectively collected data are available, based on our experiences to date, we suggest a lower threshold to perform CT angiography in patients COVID-19 pneumonia, particularly in those with a prolonged history of illness and immobility before admission, grossly elevated D-dimer, lack of improvement or clinical deterioration with increasing oxygen requirement.

Bronchiectasis is a well-recognised complication of primary antibody deficiency (PAD) syndromes. Previous data suggest that mortality in common variable immune deficiency (CVID) is not associated with isolated bronchiectasis. A retrospective analysis of patients with CVID and specific antibody deficiency in two tertiary referral centres with lung disease was conducted. Severity of bronchiectasis at presentation was associated with mortality. Lower FEV1, colonisation with Pseudomonas aeruginosa and a diagnosis of COPD were also associated with mortality. Bronchiectasis is an important driver of mortality in patients with PAD syndromes.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria ( n  = 59 for molnupiravir and n  = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.