A bacteriophage cocktail targeting Yersinia pestis provides strong post-exposure protection in a rat pneumonic plague model.

Yersinia pestis, one of the deadliest bacterial pathogens ever known, is responsible for three plague pandemics and several epidemics, with over 200 million deaths during recorded history. Due to high genomic plasticity, Y. pestis is amenable to genetic mutations as well as genetic engineering that can lead to the emergence or intentional development of pan-drug-resistant strains. Indeed, antibiotic-resistant strains (e.g., strains carrying multidrug-resistant or MDR plasmids) have been isolated in various countries and endemic areas. Thus, there is an urgent need to develop novel, safe, and effective treatment approaches for managing Y. pestis infections. This includes infections by antigenically distinct strains for which vaccines (none FDA approved yet) may not be effective and those that cannot be managed by currently available antibiotics. Lytic bacteriophages provide one such alternative approach. In this study, we examined post-exposure efficacy of a bacteriophage cocktail, YPP-401, to combat pneumonic plague caused by Y. pestis CO92. YPP-401 is a four-phage preparation effective against a panel of at least 68 genetically diverse Y. pestis strains. Using a pneumonic plague aerosol challenge model in gender-balanced Brown Norway rats, YPP-401 demonstrated ~88% protection when delivered 18 h post-exposure for each of two administration routes (i.e., intraperitoneal and intranasal) in a dose-dependent manner. Our studies provide proof-of-concept that YPP-401 could be an innovative, safe, and effective approach for managing Y. pestis infections, including those caused by naturally occurring or intentionally developed multidrug-resistant strains.IMPORTANCECurrently, there are no FDA-approved plague vaccines. Since antibiotic-resistant strains of Y. pestis have emerged or are being intentionally developed to be used as a biothreat agent, new treatment modalities are direly needed. Phage therapy provides a viable option against potentially antibiotic-resistant strains. Additionally, phages are nontoxic and have been approved by the FDA for use in the food industry. Our study provides the first evidence of the protective effect of a cocktail of four phages against pneumonic plague, the most severe form of disease. When treatment was initiated 18 h post infection by either the intranasal or intraperitoneal route in Brown Norway rats, up to 87.5% protection was observed. The phage cocktail had a minimal impact on a representative human microbiome panel, unlike antibiotics. This study provides strong proof-of-concept data for the further development of phage-based therapy to treat plague.

The More You See, the More Confusion: Two Cases of Pneumonia With Confusing Imaging Findings of Adenocarcinoma.

Imaging studies are a helpful tool when facing pulmonary pathology. While a specific radiologic pattern suggests a diagnosis, a multidisciplinary approach is ideal. Pneumonia and lung adenocarcinoma (LADC) are among the leading causes of morbidity and mortality worldwide. LADC has many patterns on computed tomography (CT); when it manifests as parenchymal consolidation, it is often difficult to distinguish from pneumonia, leading to a delayed or erroneous diagnosis. To achieve a definite diagnosis, clinical information, imaging, and laboratory findings are required. We present two cases that illustrate the importance of applying image interpretation to clinical context. In the first case CT was suspicious for pulmonary malignancy, after a failed response to antibiotics, subsequent invasive interventions led to infection dissemination and complicated clinical course. In the second case, CT showed similar imaging findings to those observed in case one. In case two, however, a conservative approach led to optimal outcomes and improved quality of care.

Yersinia pestis and pneumonic plague: Insight into how a lethal pathogen interfaces with innate immune populations in the lung to cause severe disease.

Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague. The historical importance and potential of plague to re-emerge as a threat worldwide are indisputable. The most severe manifestion of plague is pneumonic plague, which results in disease that is 100% lethal without treatment. Y. pestis suppresses host immune responses early in the lung to establish infection. The later stages of infection see the rapid onset of hyperinflammatory responses that prove lethal. The study of Y. pestis host/pathogen interactions have largely been investigated during bubonic plague and with attenuated strains in cell culture models. There remains a somewhat limited understanding of the interactions between virulent Y. pestis and immune populations in the lung that drive severe disease. In this review we give a broad overview of the progression of pneumonic plague and highlighting how Y. pestis interfaces with host innate immune populations in the lung to cause lethal disease.

Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague.

Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

Pneumonic-type lung adenocarcinoma with KRAS G12V mutation and sustained response to Afatinib.

BACKGROUND: Pneumonic-type lung adenocarcinoma (P-ADC) is a rare and challenging subtype of primary lung cancer that can be difficult to distinguish from pneumonia based on radiological images. Furthermore, no drugs are currently available that specifically target KRAS G12V. CASE PRESENTATION: Here we report a case of P-ADC with typical and informative imaging features throughout the course of the disease, including patchy shadows, high-density lesions with aerated bronchus, diffuse ground-glass opacities, and nodular shadows from computed tomography (CT) scan. The KRAS G12V mutation was detected using Next-generation sequencing (NGS). An individualized Afatinib-based therapeutic schedule was prescribed and achieved sustained response after multiple lines of treatment had failed. CONCLUSION: Our case highlights the typical and dynamic changes in imaging features of P-ADC and provides an indicative treatment strategy for KRAS G12V-mutated lung adenocarcinoma.

Multiple Introductions of Yersinia pestis during Urban Pneumonic Plague Epidemic, Madagascar, 2017.

Pneumonic plague (PP) is characterized by high infection rate, person-to-person transmission, and rapid progression to severe disease. In 2017, a PP epidemic occurred in 2 Madagascar urban areas, Antananarivo and Toamasina. We used epidemiologic data and Yersinia pestis genomic characterization to determine the sources of this epidemic. Human plague emerged independently from environmental reservoirs in rural endemic foci >20 times during August-November 2017. Confirmed cases from 5 emergences, including 4 PP cases, were documented in urban areas. Epidemiologic and genetic analyses of cases associated with the first emergence event to reach urban areas confirmed that transmission started in August; spread to Antananarivo, Toamasina, and other locations; and persisted in Antananarivo until at least mid-November. Two other Y. pestis lineages may have caused persistent PP transmission chains in Antananarivo. Multiple Y. pestis lineages were independently introduced to urban areas from several rural foci via travel of infected persons during the epidemic.

The efficacy, safety, and immunogenicity of plague vaccines: A systematic literature review.

Plague remains endemic in many parts of the world, and despite efforts, no preventative vaccine is available. We performed a systemic review of available randomised controlled trials (RCTs) of live, attenuated, or killed plague vaccines vs. placebo, no intervention, or other plague vaccine to evaluate their efficacy, safety, and immunogenicity. Data sources included MEDLINE, Embase, and the Cochrane Library; clinical trial registers; and reference lists of included studies. Primary outcomes were efficacy, safety, and immunogenicity. Risk of bias was assessed using the Cochrane Collaborations tool. Only 2 RCTs, both on subunit vaccines, were included out of the 75 screened articles. The 2 trials included 240 participants with a follow-up of 3 months and 60 participants with a follow-up of 13 months, respectively. Safety evidence was limited, but both vaccines were well tolerated, with only mild to moderate adverse events. Both vaccines were immunogenic in a dose-dependent manner. However, given the limited data identified in this systematic review, we are unable to quantify the efficacy of vaccines to prevent plague, as well as their long-term safety and immunogenicity. More trials of plague vaccines are needed to generate additional evidence of their long-term effects.

Manganese-Based Nanoparticle Vaccine for Combating Fatal Bacterial Pneumonia.

Bacterial pneumonia is the leading cause of death worldwide among all infectious diseases. However, currently available vaccines against fatal bacterial lung infections, e.g., pneumonic plague, are accompanied by limitations, including insufficient antigen-adjuvant co-delivery and inadequate immune stimulation. Therefore, there is an urgent requirement to develop next-generation vaccines to improve the interaction between antigen and adjuvant, as well as enhance the effects of immune stimulation. This study develops a novel amino-decorated mesoporous manganese silicate nanoparticle (AMMSN) loaded with rF1-V10 (rF1-V10@AMMSN) to prevent pneumonic plague. These results suggest that subcutaneous immunization with rF1-V10@AMMSN in a prime-boost strategy induces robust production of rF1-V10-specific IgG antibodies with a geometric mean titer of 315,844 at day 42 post-primary immunization, which confers complete protection to mice against 50 × LD50 of Yersinia pestis (Y. pestis) challenge via the aerosolized intratracheal route. Mechanistically, rF1-V10@AMMSN can be taken up by dendritic cells (DCs) and promote DCs maturation through activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and production of type I interferon. This process results in enhanced antigen presentation and promotes rF1-V10-mediated protection against Y. pestis infection. This manganese-based nanoparticle vaccine represents a valuable strategy for combating fatal bacterial pneumonia.

Evaluation of CT features for differentiating consolidation pattern of pulmonary MALT lymphoma from pneumonic-type lung adenocarcinoma.

Purpose: In clinical practice, the consolidation pattern of pulmonary mucosa-associated lymphoid tissue (C-MALT) was often misdiagnosed as pneumonic-type lung adenocarcinoma (P-LADC). However, the mainstay of treatment and prognosis of these two diseases are different. The purpose of this study was to distinguish C-MALT from P-LADC by pre-treatment chest computed tomography (CT) features. Patients and methods: A total of 31 patients with C-MALT (15 men and 16 women; mean age, 61.1 ± 11.2 years) and 58 patients with P-LADC (34 men and 24 women; mean age, 68.6 ± 7.4 years) confirmed by pathology who underwent contrast-enhanced chest CT were retrospectively enrolled from September 2014 to February 2023. Detailed clinical and CT characteristics of the two groups were evaluated. Logistic regression analysis was used to assess the effectiveness of statistically significant variables in distinguishing C-MALT from P-LADC. Results: The average age of C-MALT was younger than P-LADC patients (p<0.001). With regard to CT features, bronchiectasis within the consolidation was more common in the C-MALT group than the P-LADC group [83.87% (26 of 31) vs 20.69% (12 of 58), p<0.001]; whereas lymph nodes enlargement [75.86% (44 of 58) vs 9.68% (3 of 31), p<0.001] and pleural effusion [43.10% (25of 58) vs 19.35% (6 of 31), p=0.025] were more frequently observed in the P-LADC group than C-MALT group. The predictors with p<0.05 (age, bronchiectasis, lymph node enlargement, and pleural effusion) were used to construct a logistic regression model in discriminating C-MALT from P-LADC, the area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), specificity, sensitivity, and accuracy were 0.9555, 86.67%, 91.53%, 83.87%, 93.10%, and 89.89%, respectively. Conclusion: C-MALT and P-LADC have differential clinical and CT features. An adequate understanding of these different characteristics can contribute to the early accurate diagnosis of C-MALT and provide an appropriate therapeutic strategy.

Ceftobiprole Medocaril Is an Effective Post-Exposure Treatment in the Fischer 344 Rat Model of Pneumonic Tularemia.

Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model.

Pulmonary Expression of Interleukin-17 Contributes to Neutrophil Infiltration into the Lungs during Pneumonic Plague.

Inhalation of respiratory droplets infected with Yersinia pestis results in a rapidly progressing and lethal necrotic pneumonia called primary pneumonic plague. Disease manifests as biphasic, with an initial preinflammatory phase with rapid bacterial replication in the lungs absent readily detectable host immune responses. This is followed by the onset of a proinflammatory phase that sees the dramatic upregulation of proinflammatory cytokines and extensive neutrophil accumulation in the lungs. The plasminogen activator protease (Pla) is an essential virulence factor that is responsible for survival of Y. pestis in the lungs. Our lab recently showed that Pla functions as an adhesin that promotes binding to alveolar macrophages to facilitate translocation of effector proteins called Yops into the cytosol of target host cells via a type 3 secretion system (T3SS). Loss of Pla-mediated adherence disrupted the preinflammatory phase of disease and resulted in early neutrophil migration to the lungs. While it is established that Yersinia broadly suppresses host innate immune responses, it is not clear precisely which signals need to be inhibited to establish a preinflammatory stage of infection. Here, we show that early Pla-mediated suppression of Interleukin-17 (IL-17) expression in alveolar macrophages and pulmonary neutrophils limits neutrophil migration to the lungs and aids in establishing a preinflammatory phase of disease. In addition, IL-17 ultimately contributes to neutrophil migration to the airways that defines the later proinflammatory phase of infection. These results suggest that the pattern of IL-17 expression contributes to the progression of primary pneumonic plague.

Mechanism of pulmonary plague biphasic syndrome: inhibition or activation of NF-κB signaling pathway.

Background: Pneumonic plague is a fatal respiratory disease caused by Yersinia pestis. Time-course transcriptome analysis on the mechanism of pneumonic plague biphasic syndrome is lacking in the literature. Materials & methods: This study documented the disease course through bacterial load, histopathology, cytokine levels and flow cytometry. RNA-sequencing technology was used to investigate the global transcriptome profile of lung tissue in mice infected with Y. pestis. Results: Inflammation-related genes were significantly upregulated at 48 h post-infection, while genes related to cell adhesion and cytoskeletal structure were downregulated. Conclusion: NOD-like receptor and TNF signaling pathways play a plausible role in pneumonic plague biphasic syndrome and lung injury by controlling the activation and inhibition of the NF-κB signaling pathway.

Pulmonary Adenocarcinoma Mimicking Pneumonia in a Young Adult.

Lung cancer is the third most common cancer in the United States. Lung adenocarcinoma is a subtype of non-small cell lung cancer. On computed tomography (CT) it can appear as ground glass nodules, consolidative opacity, or solid mass lesions located in the periphery. Because it can appear as a consolidation, it can sometimes be confused with an infectious process such as pneumonia. We present a case of a 27-year-old male initially diagnosed with pneumonia; however, three months later, when he presented to the hospital with worsening pleuritic chest pain, fever, and dyspnea after a bronchoscopy a week before admission, pathology was positive for adenocarcinoma.

Rapid Induction of Protective Immunity against Pneumonic Plague by Yersinia pestis Polymeric F1 and LcrV Antigens.

In a recent study, we demonstrated that vaccination with the polymeric F1 capsule antigen of the plague pathogen Yersinia pestis led to the rapid induction of a protective humoral immune response via the pivotal activation of innate-like B1b cells. Conversely, the monomeric version of F1 failed to promptly protect vaccinated animals in this model of the bubonic plague. In this study, we examined the ability of F1 to confer the rapid onset of protective immunity in the more challenging mouse model of the pneumonic plague. Vaccination with one dose of F1 adsorbed on aluminum hydroxide elicited effective protection against subsequent lethal intranasal exposure to a fully virulent Y. pestis strain within a week. Interestingly, the addition of the LcrV antigen shortened the time required for achieving such rapid protective immunity to 4-5 days after vaccination. As found previously, the polymeric structure of F1 was essential in affording the accelerated protective response observed by covaccination with LcrV. Finally, in a longevity study, a single vaccination with polymeric F1 induced a higher and more uniform humoral response than a similar vaccination with monomeric F1. However, in this setting, the dominant contribution of LcrV to long-lasting immunity against a lethal pulmonary challenge was reiterated.

Differentiation of localized pneumonic-type lung adenocarcinoma from localized pulmonary inflammatory lesion based on clinical data and multi-slice spiral computed tomography imaging features.

Background: Localized pneumonic-type lung adenocarcinoma (L-PLADC) is a special type of lung adenocarcinoma, which mimicking localized pulmonary inflammatory lesion (L-PIL), and many delayed diagnoses of L-PLADC have been identified due to insufficient clinical understanding or the lack of knowledge regarding the radiological findings. Multi-slice spiral computed tomography (MSCT) not only observes the fine structure of the lesion clearly, but also can evaluate the lesion and its surrounding tissues more intuitively, stereoscopically, and accurately using a variety of reconstruction techniques. The present study aimed to investigate the diagnostic value of clinical data and MSCT imaging features in differentiating L-PLADC from L-PIL. Methods: The clinical data and chest MSCT imaging features of 71 patients with L-PLADC and 70 patients with L-PIL were retrospectively analyzed. Seventy-one patients with L-PLADC underwent surgical resection or puncture and were confirmed as having invasive adenocarcinoma by pathology. Seventy patients with L-PIL were confirmed by clinical anti-inflammatory treatment or by puncture and surgery. The Chi-square and Mann-Whitney U tests were used to analyze the clinical data and MSCT imaging features of the included patients. Variables with P<0.05 in the univariate analysis were included in the multivariate logistic regression analysis to determine the independent risk factors for the diagnosis of L-PLADC. Results: The clinical data analysis showed that multivariate logistic regression analysis showed that irregular air bronchogram [odds ratio (OR) =15.946; P<0.001], ground-glass opacity (GGO) component (OR =12.369; P<0.001), pleural traction (OR =10.982; P<0.001), necrosis (OR =0.078; P<0.001), adjacent bronchial wall thickening (OR =0.017; P<0.001), pleural thickening (OR =0.074; P<0.001), and respiratory symptoms were independent risk factors for the diagnosis of L-PLADC [OR =0.117; the area under the curve (AUC), sensitivity, specificity, and accuracy values were 0.989, 97.2%, 94.3%, and 95.7%, respectively]. Conclusions: L-PLADC and L-PIL exhibit different clinical and MSCT imaging features. Determining these characteristics is conducive to the early diagnosis and clinical treatment of L-PLADC.

Intrapleural Urokinase Injection after Medical Thoracoscopy for Empyema and Complicated Para-Pneumonic Effusion: A Case Series.

Empyema and complicated para-pneumonic effusion (CPPE) often require surgical intervention because of insufficient antibiotic effect and chest tube drainage. From January 2017 to September 2021, we encountered seven patients who underwent intrapleural urokinase injection after medical thoracoscopy for the treatment of empyema or CPPE. None of the seven patients required further surgical interventions or showed any complications associated with the therapeutic procedures. The combined use of intrapleural urokinase injections and medical thoracoscopy may be an effective and safe therapeutic option for the management of empyema and CPPE.

Diagnosis and prognosis of acute respiratory distress syndrome related to diffuse pneumonic-type adenocarcinoma: a single-center case series study.

Background: The absence of diagnosis of acute respiratory distress syndrome (ARDS) concerns 20% of cancer patients and is associated with poorer outcomes. Diffuse pneumonic-type adenocarcinoma (P-ADC) is part of these difficult-to-diagnose ARDS, but only limited data are available regarding critically ill patients with diffuse P-ADC. We sought to describe the diagnosis process and the prognosis of P-ADC related ARDS patients admitted to the intensive care unit (ICU). Methods: Single-center observational case series study. All consecutive patients admitted to the ICU over a two-decade period presenting with (I) histologically or cytologically proven adenocarcinoma of the lung and (II) ARDS according to Berlin definition were included. Clinical, biological, radiological and cytological features of P-ADC were collected to identify diagnostic clues. Multivariate logistic regression analyses were performed to assess factors associated with ICU and hospital mortality. Results: Among the 24 patients included [70 (61-75) years old, 17 (71%) males], the cancer diagnosis was performed during the ICU stay in 19 (79%), and 17 (71%) required mechanical ventilation. The time between the first symptoms and the diagnosis of P-ADC was 210 days (92-246 days). A non-resolving pneumonia after 2 (2 to 3) antibiotics lines observed in 23 (96%) patients with a 34 mg/L (19 to 75 mg/L) plasma C-reactive protein level at ICU admission. Progressive dyspnea, bronchorrhea, salty expectoration, fissural bulging and compressed bronchi and vessels were present in 100%, 83%, 69%, 57% and 43% of cases. Cytological examination of sputum or broncho-alveolar lavage provided a 75% diagnostic yield. The ICU and hospital mortality rates were 25% and 63%, respectively. The time (in days) between first symptoms and diagnosis [odds ratio (OR) 1.02, 95% confidence interval (95% CI): 1.00-1.03, P=0.046] and the Simplified Acute Physiology Score II (OR 1.16, 95% CI: 1.01-1.33, P=0.040) were independently associated with ICU mortality. Conclusions: Non-resolving pneumonia after several antibiotics lines without inflammatory syndrome, associated with progressive dyspnea, salty bronchorrhea, and lobar swelling (i.e., fissural bulging, compressed bronchi and vessels) were suggestive of P-ADC. Delayed diagnosis of diffuse P-ADC seemed an independent prognostic predictor and disease timely recognition may contribute to prognosis improvement.

Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: A prospective cohort study.

Background: The emergence of COVID-19 and public health measures implemented to reduce SARS-CoV-2 infections have both affected acute lower respiratory tract disease (aLRTD) epidemiology and incidence trends. The severity of COVID-19 and non-SARS-CoV-2 aLRTD during this period have not been compared in detail. Methods: We conducted a prospective cohort study of adults age ≥18 years admitted to either of two acute care hospitals in Bristol, UK, from August 2020 to November 2021. Patients were included if they presented with signs or symptoms of aLRTD (e.g., cough, pleurisy), or a clinical or radiological aLRTD diagnosis. Findings: 12,557 adult aLRTD hospitalisations occurred: 10,087 were associated with infection (pneumonia or non-pneumonic lower respiratory tract infection [NP-LRTI]), 2161 with no infective cause, with 306 providing a minimal surveillance dataset. Confirmed SARS-CoV-2 infection accounted for 32% (3178/10,087) of respiratory infections. Annual incidences of overall, COVID-19, and non- SARS-CoV-2 pneumonia were 714.1, 264.2, and 449.9, and NP-LRTI were 346.2, 43.8, and 302.4 per 100,000 adults, respectively. Weekly incidence trends in COVID-19 aLRTD showed large surges (median 6.5 [IQR 0.7-10.2] admissions per 100,000 adults per week), while other infective aLRTD events were more stable (median 14.3 [IQR 12.8-16.4] admissions per 100,000 adults per week) as were non-infective aLRTD events (median 4.4 [IQR 3.5-5.5] admissions per 100,000 adults per week). Interpretation: While COVID-19 disease was a large component of total aLRTD during this pandemic period, non- SARS-CoV-2 infection still caused the majority of respiratory infection hospitalisations. COVID-19 disease showed significant temporal fluctuations in frequency, which were less apparent in non-SARS-CoV-2 infection. Despite public health interventions to reduce respiratory infection, disease incidence remains high. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Protection Induced by Oral Vaccination with a Recombinant Yersinia pseudotuberculosis Delivering Yersinia pestis LcrV and F1 Antigens in Mice and Rats against Pneumonic Plague.

A newly attenuated Yersinia pseudotuberculosis strain (designated Yptb1) with triple mutation Δasd ΔyopK ΔyopJ and chromosomal insertion of the Y. pestis caf1R-caf1M-caf1A-caf1 operon was constructed as a live vaccine platform. Yptb1 tailored with an Asd+ plasmid (pYA5199) (designated Yptb1[pYA5199]) simultaneously delivers Y. pestis LcrV and F1. The attenuated Yptb1(pYA5199) localized in the Peyer's patches, lung, spleen, and liver for a few weeks after oral immunization without causing any disease symptoms in immunized rodents. An oral prime-boost Yptb1(pYA5199) immunization stimulated potent antibody responses to LcrV, F1, and Y. pestis whole-cell lysate (YPL) in Swiss Webster mice and Brown Norway rats. The prime-boost Yptb1(pYA5199) immunization induced higher antigen-specific humoral and cellular immune responses in mice than a single immunization did, and it provided complete short-term and long-term protection against a high dose of intranasal Y. pestis challenge in mice. Moreover, the prime-boost immunization afforded substantial protection for Brown Norway rats against an aerosolized Y. pestis challenge. Our study highlights that Yptb1(pYA5199) has high potential as an oral vaccine candidate against pneumonic plague.

A Comparative Study of the Safety and Efficacy of Intrapleural Fibrinolysis With Streptokinase and Urokinase in the Management of Loculated Pleural Effusions.

Background Intrapleural fibrinolytic therapy (IPFT) with streptokinase (STK), urokinase (UK), and alteplase remains a common practice for managing loculated pleural effusions (LPEs). However, very limited data are available on the comparative efficacy of these agents. Methodology We compared the efficacy and safety of intrapleural streptokinase (n = 28) and urokinase (n = 38) in 66 patients with loculated effusions. IPFT was initiated if effusion remained undrained despite the placement of intercostal chest drainage or pigtail catheter. The dose of STK and UK were 250,000 IU twice daily and 100,000 IU once daily, respectively. The volume of fluid drained after IPFT, radiologic response, clinical response, and adverse events were compared between the two groups. Results The mean volume of fluid drained post-IPFT was 1,379 mL in the STK arm and 1,110 mL in the UK arm (p = 0.251). Of the 66 patients, 53 (80.3%) had good clinical response, and 28 (43.7%) had >75% resolution of effusion on chest radiographs. The clinical (79% vs. 82%; p = 0.765) and radiologic response rates (39.3% vs. 44.6%; p = 0.568) were similar in both STK and UK arms. Pain was the most common adverse event in both groups. Significantly more patients in the STK arm developed fever (14% vs. 0%, p = 0.030). Treatment-limiting adverse events occurred in five patients. Conclusions IPFT is a safe and effective method for managing patients with LPEs. Although the clinical and radiologic response rates were similar with STK and UK, the latter may be the preferred choice because of its better safety profile and ease of administration (once-daily dose).