[Pay attention to new evolution trends in the etiology of community-acquired pneumonia in adults].

Over the past two to three decades, the emergence and re-emergence of new infectious diseases, advances in molecular detection techniques of pathogens, antibiotic resistance, changes in population lifestyle and immune status (including vaccination), and other factors have led to new evolutions in the etiology of community-acquired pneumonia (CAP). (1) Although Streptococcus pneumoniae remains a common pathogen of CAP, it is no longer the leading cause in China and the United States. According to the results of 2 multicenter studies in China in the early 21st century, Streptococcus pneumoniae accounted for 10.3% and 12.0% of adult CAP pathogens, respectively, ranking second. A study on key pathogens of adult CAP in nine cities in mainland China from 2014 to 2019 using real-time quantitative PCR and conventional culture on respiratory and blood specimens showed an overall prevalence of Streptococcus pneumoniae of 7.43%, ranking sixth. However, its ranking varied from third to seventh among the nine cities. (2) Challenges and concerns about viruses have increased. National surveillance of acute respiratory tract infections and epidemiology in China from 2009 to 2019 indicated that the positivity rates for viral infections in adult pneumonia was 20.5%. These rates were similar to the results of the CDC's CAP pathogen study in the United States, although the rankings were different (viruses ranked second in China and first in the United States). Over the past 20 years, the emergence of new viral respiratory infections caused by mutant strains or zoonotic strains has significantly increased the challenges and threats posed by viral respiratory infections. (3) The role of Mycoplasma pneumoniae (M pneumoniae) in adult CAP and the need for routine empirical antibiotic coverage are controversial. In addition to the influence of epidemic cycles, the prevalence of M pneumoniae is influenced by factors such as age, season, study design, and detection methods, and geographical distribution is also an important influencing factor. Although M. pneumoniae ranks first among CAP pathogens in mainland China (11.05%), there are significant regional differences. In Beijing, Xi'an, and Changchun M. pneumoniae ranks first, while in Harbin, Nanjing, and Fuzhou it ranks second to sixth. In Wuhan, Shenzhen, and Chengdu M. pneumoniae ranks after the tenth position. Available evidence supports the notion that routine coverage of M. pneumoniae is not necessary for empirical treatment of CAP, except in severe cases. In regions with a high prevalence of M. pneumoniae, the decision to cover atypical pathogens in patients with mild to moderate CAP should be based on local data and individualized. (4) CAP caused by multidrug-resistant bacteria, especially multidrug-resistant Gram-negative bacilli (GNB), has become a concern. According to a systematic review of Chinese literature, Klebsiella pneumoniae accounted for 8.12% of adult CAP patients, ranking fifth, and Pseudomonas aeruginosa accounted for 4.7% (ninth). The China Antimicrobial Resistance Surveillance System (CARSS) reported an average resistance rate of 27.7% for Klebsiella pneumoniae to third-generation cephalosporins and a resistance rate of 10.0% to carbapenems in 2021. The average resistance rate of Pseudomonas aeruginosa to carbapenems was 16.6%. Early empirical treatment should consider predicting the resistance profile using a "locally validated risk factor" scoring system. (5) Co-infections are common but under-reported. The development of non-culture detection techniques over the past 40 years has significantly increased the detection rate of respiratory pathogens, especially viruses, leading to an increasing number of reports of bacterial-viral co-infections in CAP. It has been reported that co-infections account for 39% of severe CAP cases on ventilators in the ICU. Currently, there is inconsistency and confusion regarding the definition and concept of co-infection, the choice of detection techniques, and the differentiation between co-detection and co-infection. Many reports of co-infections in COVID-19 lacked pathogenic evidence, and some even listed "effective antibiotic treatment" as one of the diagnostic criteria for viral-bacterial co-infections, suggesting to some extent an overuse of antibiotics in COVID-19. Due to the diverse etiological spectrum of CAP between regions in the recent years, it is challenging to develop unified guidelines for the management of CAP in large countries. This article provides recommendations for the development of local guidelines for the diagnosis and treatment of CAP.

Exploring the microbiota difference of bronchoalveolar lavage fluid between community-acquired pneumonia with or without COPD based on metagenomic sequencing: a retrospective study.

BACKGROUND: Community-acquired pneumonia (CAP) patients with chronic obstructive pulmonary disease (COPD) have higher disease severity and mortality compared to those without COPD. However, deep investigation into microbiome distribution of lower respiratory tract of CAP with or without COPD was unknown. METHODS: So we used metagenomic next generation sequencing (mNGS) to explore the microbiome differences between the two groups. RESULTS: Thirty-six CAP without COPD and 11 CAP with COPD cases were retrieved. Bronchoalveolar lavage fluid (BALF) was collected and analyzed using untargeted mNGS and bioinformatic analysis. mNGS revealed that CAP with COPD group was abundant with Streptococcus, Prevotella, Bordetella at genus level and Cutibacterium acnes, Rothia mucilaginosa, Bordetella genomosp. 6 at species level. While CAP without COPD group was abundant with Ralstonia, Prevotella, Streptococcus at genus level and Ralstonia pickettii, Rothia mucilaginosa, Prevotella melaninogenica at species level. Meanwhile, both alpha and beta microbiome diversity was similar between groups. Linear discriminant analysis found that pa-raburkholderia, corynebacterium tuberculostearicum and staphylococcus hominis were more enriched in CAP without COPD group while the abundance of streptococcus intermedius, streptococcus constellatus, streptococcus milleri, fusarium was higher in CAP with COPD group. CONCLUSIONS: These findings revealed that concomitant COPD have an mild impact on lower airway microbiome of CAP patients.

Neglected Mycobacterium Avium Complex Infection in a Patient with Prolonged Pneumonia.

BACKGROUND: Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the infecting pathogen is crucial for subsequent treatment. We report a case of NTM-PD in a healthy middle-aged female with Mycobacterium tuberculosis complex group (MAC) infection confirmed by mNGS examination. METHODS: Appropriate laboratory tests, chest CT scan, bronchoscopic alveolar lavage fluid (BALF) examination, and macrogenomic next-generation sequencing (mNGS) were performed to establish the diagnosis. RESULTS: Chest CT showed multiple inflammatory lesions in the right middle lobe, and BALF sent for mNGS finally confirmed the diagnosis of MAC infection. After symptomatic treatment with azithromycin combined with ethambutol and rifampicin, the patient improved and was discharged from the hospital. CONCLUSIONS: In patients with pulmonary infections, pathogens should be clarified early to determine the diagnosis. mNGS of BALF samples have high specificity in detecting pathogens of infectious diseases, especially complex mixed infectious disease pathogens.

Microbial variations in sputum cultures among hospitalized patients with community-acquired pneumonia: differences in sputum microbiota between asthma and COPD patients.

OBJECTIVE: To assess differences in the sputum microbiota of community-acquired pneumonia (CAP) patients with either COPD or asthma, specifically focusing on a patient population in Turkey. METHODS: This retrospective study included hospitalized patients > 18 years of age with a diagnosis of pneumonia between January of 2021 and January of 2023. Participants were recruited from two hospitals, and three patient groups were considered: CAP patients with asthma, CAP patients with COPD, and CAP patients without COPD or asthma. RESULTS: A total of 246 patients with CAP were included in the study, 184 (74.8%) and 62 (25.2%) being males and females, with a mean age of 66 ± 14 years. Among the participants, 52.9% had COPD, 14.2% had asthma, and 32.9% had CAP but no COPD or asthma. Upon analysis of sputum cultures, positive sputum culture growth was observed in 52.9% of patients. The most commonly isolated microorganisms were Pseudomonas aeruginosa (n = 40), Acinetobacter baumannii (n = 20), Klebsiella pneumoniae (n = 16), and Moraxella catarrhalis (n = 8). CAP patients with COPD were more likely to have a positive sputum culture (p = 0.038), a history of antibiotic use within the past three months (p = 0.03), utilization of long-term home oxygen therapy (p < 0.001), and use of noninvasive ventilation (p = 0.001) when compared with the other patient groups. Additionally, CAP patients with COPD had a higher CURB-65 score when compared with CAP patients with asthma (p = 0.004). CONCLUSIONS: This study demonstrates that CAP patients with COPD tend to have more severe presentations, while CAP patients with asthma show varied microbial profiles, underscoring the need for patient-specific management strategies in CAP.

Ochrobactrum Anthropi; an Unusual Cause of Bacteremia and Pneumonia: A Case Report and a Brief Review of the Literature.

Background: Ochrobactrum anthropi spp. is a non-enteric, aerobic gram-negative bacillus that has been reported to cause sepsis and occasionally bacteremia in both immunocompetent and immunocompromised hosts. This bacterium is capable of surviving in various habitats, but due to its affinity for aqueous environments, O. anthropi is hypothesized to have an affinity for indwelling plastic devices and other foreign bodies.

Case Presentation: We report a case of a 66 y/o male with a history of polysubstance abuse disorder admitted for toxic metabolic encephalopathy and found to have bronchopneumonia and bacteremia secondary to O. anthropi infection resulting in sepsis and cardiopulmonary arrest.

Discussion: Ochrobactrum spp. is an unusual pathogen of low virulence and has been noted to cause bacteremia and occasionally sepsis in both immunocompetent and immunosuppressed patients. Isolation of this pathogen in the appropriate setting should be considered a true pathogen and treated as such to avoid sequela of this infection.

Conclusion: This case report and literature review suggest that Ochrobactrum anthropi appears more frequently as a pathogen in nosocomial infections than suggested in the literature.

Pulmonary Infection.

Pneumonia is a significant cause of morbidity and mortality in the community and hospital settings. Bacterial, viral, mycobacterial, and fungal pathogens are all potential causative agents of pulmonary infection. Chest radiographs and computed tomography are frequently utilized in the assessment of pneumonia. Learning the imaging patterns of different potential organisms allows the radiologist to formulate an appropriate differential diagnosis. An organism-based approach is used to discuss the imaging findings of different etiologies of pulmonary infection.

Highly diverse sputum microbiota correlates with the disease severity in patients with community-acquired pneumonia: a longitudinal cohort study.

BACKGROUND: Community-acquired pneumonia (CAP) is a common and serious condition that can be caused by a variety of pathogens. However, much remains unknown about how these pathogens interact with the lower respiratory commensals, and whether any correlation exists between the dysbiosis of the lower respiratory microbiota and disease severity and prognosis. METHODS: We conducted a retrospective cohort study to investigate the composition and dynamics of sputum microbiota in patients diagnosed with CAP. In total, 917 sputum specimens were collected consecutively from 350 CAP inpatients enrolled in six hospitals following admission. The V3-V4 region of the 16 S rRNA gene was then sequenced. RESULTS: The sputum microbiota in 71% of the samples were predominately composed of respiratory commensals. Conversely, 15% of the samples demonstrated dominance by five opportunistic pathogens. Additionally, 5% of the samples exhibited sterility, resembling the composition of negative controls. Compared to non-severe CAP patients, severe cases exhibited a more disrupted sputum microbiota, characterized by the highly dominant presence of potential pathogens, greater deviation from a healthy state, more significant alterations during hospitalization, and sparser bacterial interactions. The sputum microbiota on admission demonstrated a moderate prediction of disease severity (AUC = 0.74). Furthermore, different pathogenic infections were associated with specific microbiota alterations. Acinetobacter and Pseudomonas were more abundant in influenza A infections, with Acinetobacter was also enriched in Klebsiella pneumoniae infections. CONCLUSION: Collectively, our study demonstrated that pneumonia may not consistently correlate with severe dysbiosis of the respiratory microbiota. Instead, the degree of microbiota dysbiosis was correlated with disease severity in CAP patients.

Associations of cold-inducible RNA-binding protein with bacterial load, proinflammatory cytokines and mortality from pneumonia.

Cold-inducible RNA-binding protein (CIRP) is a damage-associated molecular pattern that plays a critical role in triggering inflammatory responses. It remains unknown whether CIRP is strongly associated with bacterial load, inflammatory response, and mortality in sepsis model. Pneumonia was induced in specific pathogen-free 8-9-week old male rats by injecting bacteria via puncture of the tracheal cartilage. The expressions of CIRP and proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß] in lung tissues, alveolar macrophages (AMs), plasma, and bronchoalveolar lavage fluid (BALF) were determined by reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The numbers of bacteria recovered from the lungs were correlated with the bacterial loads injected and mortality. The expressions of CIRP increased sharply as the bacterial loads increased in the lung tissues and AMs. The amounts of TNF-α, IL-6 and IL-1ß proteins synthesized were dependent on the bacterial load in the lung tissues. Releases of CIRP, TNF-α, IL-6, and IL-1ß increased with the bacterial load in the blood plasma. The proteins confirmed similar patterns in the BALF. CIRP was strongly associated with the releases of TNF-α, IL-6, and IL-1ß in the lung tissues, blood plasma, and BALF, and showed a close correlation with mortality. CIRP demonstrated a strong association with bacterial load, which is new evidence, and close correlations with proinflammatory cytokines and mortality of pneumonia in rats, suggesting that it might be an interesting pneumonic biomarker for monitoring host response and predicting mortality, and a promising target for immunotherapy.

Weil's disease with multiple organ dysfunction, community-acquired pneumonia and septic shock: The role of rapid diagnosis and management.

Leptospirosis is an uncommon infectious illness - a spirochetal zoonosis - caused by Leptospira species and the primary cause of human leptospirosis is exposure to the urine of infected rodents. Clinical manifestations of human leptospirosis are diverse, ranging from asymptomatic infection to severe life-threatening with multiorgan dysfunction. The severe condition is known as Weil's disease, which is characterized by feverish illness with jaundice, acute kidney damage, and bleeding. The aim of this case report was to present a Weil's disease which occurred simultaneously with a community-acquired pneumonia (CAP) resulting in serious complications. A 41-year-old man with Weil's disease, as well as CAP caused by Streptococcus pneumoniae, and septic shock was presented. The patient was treated accordingly after establishing the diagnosis through history taking, physical examination, and laboratory tests. In this instance, the score for diagnosing leptospirosis based on Modified Faine's Criteria was calculated resulting possible diagnoses; and therefore, therapeutic management was initiated. Despite presenting with severe symptoms, the patient recovered completely after receiving antibiotics and supportive care. This study highlights that when a patient has Weil's disease and a CAP infection, which could cause unfavorable consequence, a prompt diagnosis and proper treatment could result satisfied patient recovery.

Evaluation of the Pneumonia Panel on laboratory samples from an Italian pediatric center: results from a monocentric study.

Lower respiratory tract infections (LRTI) are still burdened by considerable morbidity and mortality. Rapid and appropriate treatment imply knowledge of the underlying causative pathogen; while it is tempting to offer broad spectrum antibiotics, Antimicrobial Stewardship Practices invite a judicious use of the latter, especially when bacteria are not the cause. However, the epidemiology shifts to multidrug resistant (MDR) pathogens that require optimization of molecules in order to provide optimal treatment. Novel methods requiring direct sample result testing such as the Biofire Pneumonia (PN) panel have recently been made available on the market. Syndromic testing may hence provide support in the diagnosis of LRTI. There is paucity of data concerning experiences in high MDR settings, and even less concerning the performance of these panels in pediatric settings with moderate MDR prevalence. Our study highlights the optimal sensitivity and importance of support from such methods in settings burdened by MDR presence and where fast and appropriate therapy is mandatory.

Impacts of environmental factors on the aetiological diagnosis and disease severity of community-acquired pneumonia in China: a multicentre, hospital-based, observational study.

Environmental exposures are known to be associated with pathogen transmission and immune impairment, but the association of exposures with aetiology and severity of community-acquired pneumonia (CAP) are unclear. A retrospective observational study was conducted at nine hospitals in eight provinces in China from 2014 to 2019. CAP patients were recruited according to inclusion criteria, and respiratory samples were screened for 33 respiratory pathogens using molecular test methods. Sociodemographic, environmental and clinical factors were used to analyze the association with pathogen detection and disease severity by logistic regression models combined with distributed lag nonlinear models. A total of 3323 CAP patients were included, with 709 (21.3%) having severe illness. 2064 (62.1%) patients were positive for at least one pathogen. More severe patients were found in positive group. After adjusting for confounders, particulate matter (PM) 2.5 and 8-h ozone (O3-8h) were significant association at specific lag periods with detection of influenza viruses and Klebsiella pneumoniae respectively. PM10 and carbon monoxide (CO) showed cumulative effect with severe CAP. Pollutants exposures, especially PM, O3-8h, and CO should be considered in pathogen detection and severity of CAP to improve the clinical aetiological and disease severity diagnosis.

Gut microbiota intervention alleviates pulmonary inflammation in broilers exposed to fine particulate matter from broiler house.

The gut microbiota of poultry is influenced by a variety of factors, including feed, drinking water, airborne dust, and footpads, among others. Gut microbiota can affect the immune reaction and inflammation in the lungs. To investigate the effect of gut microbiota variation on lung inflammation induced by PM2.5 (fine particulate matter) in broilers, 36 Arbor Acres (AA) broilers were randomly assigned to three groups: control group (CON), PM2.5 exposure group (PM), and PM2.5 exposure plus oral antibiotics group (PMA). We used non-absorbable antibiotics (ABX: neomycin and amikacin) to modify the microbiota composition in the PMA group. The intervention was conducted from the 18th to the 28th day of age. Broilers in the PM and PMA groups were exposed to PM by a systemic exposure method from 21 to 28 days old, and the concentration of PM2.5 was controlled at 2 mg/m3. At 28 days old, the lung injury score, relative mRNA expression of inflammatory factors, T-cell differentiation, and dendritic cell function were significantly increased in the PM group compared to the CON group, and those of the PMA group were significantly decreased compared to the PM group. There were significant differences in both α and ß diversity of cecal microbiota among these three groups. Numerous bacterial genera showed significant differences in relative abundance among the three groups. In conclusion, gut microbiota could affect PM2.5-induced lung inflammation in broilers by adjusting the capacity of antigen-presenting cells to activate T-cell differentiation. IMPORTANCE: Gut microbes can influence the development of lung inflammation, and fine particulate matter collected from broiler houses can lead to lung inflammation in broilers. In this study, we explored the effect of gut microbes modified by intestinal non-absorbable antibiotics on particulate matter-induced lung inflammation. The results showed that modification in the composition of gut microbiota could alleviate lung inflammation by attenuating the ability of dendritic cells to stimulate T-cell differentiation, which provides a new way to protect lung health in poultry farms.

Role of Clinical Features, Pathogenic and Etiological Characteristics of Community-acquired Pneumonia with Type 2 Diabetes Mellitus in Early Diagnosis.

OBJECTIVE: To study the etiological characteristics of community-acquired pneumonia (CAP) combined with type 2 diabetes (T2D), providing a reference for early clinical diagnosis and treatment of the disease. METHODS: We selected a total of 93 patients with CAP and analyzed their metagenomics nextgeneration sequencing (mNGS) data. The case group comprised 46 patients with combined CAP/T2D, and the control group comprised 47 patients without diabetes. We analyzed the pathogenic findings of the two groups. RESULTS: There were statistically significant differences in age between the two groups (P = 0.001). Leukocytes (P = 0.012), blood platelets (P = 0.034), fibrinogen (P = 0.037), D-dimer (P = 0.000), calcitonin ogen (P = 0.015), ultrasensitive C-reactive protein or C-reactive protein (CRP) (P = 0.000), serum amyloid A (P = 0.000), and erythrocyte sedimentation rate (P = 0.003) were higher in the case group than in the control group. Albumin was lower in the case group than in the control group. All differences were statistically significant. The infection rates of Klebsiella pneumoniae (P = 0.030), Pseudomonas aeruginosa (P = 0.043), and Candida albicans (P = 0.032) were significantly different between the two groups. CONCLUSION: Compared with those without diabetes, the infection rates of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans were higher in patients with combined CAP/T2D.

The clinical value of mNGS of bronchoalveolar lavage fluid versus traditional microbiological tests for pathogen identification and prognosis of severe pneumonia (NT-BALF):study protocol for a prospective multi-center randomized clinical trial.

BACKGROUND: Early, rapid, and accurate pathogen diagnosis can help clinicians select targeted treatment options, thus improving prognosis and reducing mortality rates of severe pneumonia. Metagenomic next-generation sequencing (mNGS) has a higher sensitivity and broader pathogen spectrum than traditional microbiological tests. However, the effects of mNGS-based antimicrobial treatment procedures on clinical outcomes and cost-effectiveness in patients with severe pneumonia have not been evaluated. METHODS: This is a regional, multi-center, open, prospective, randomized controlled trial to evaluate that whether the combination of mNGS and traditional testing methods could decrease 28-day call-cause mortality with moderate cost-effectiveness. A total of 192 patients with severe pneumonia will be recruited from four large tertiary hospitals in China. Bronchoalveolar lavage fluid will be obtained in all patients and randomly assigned to the study group (mNGS combined with traditional microbiological tests) or the control group (traditional microbiological tests only) in a 1:1 ratio. Individualized antimicrobial treatment and strategy will be selected according to the analysis results. The primary outcome is 28-day all-cause mortality. The secondary outcomes are ICU and hospital length of stay (LOS), ventilator-free days and ICU-free days, consistency between mNGS and traditional microbiological tests, detective rate of mNGS and traditional microbiological tests, turn-out time, time from group allocation to start of treatment, duration of vasopressor support, types and duration of anti-infective regimens, source of drug-resistant bacteria or fungi, and ICU cost. DISCUSSION: The clinical benefits of mNGS are potentially significant, but its limitations should also be considered. TRIAL REGISTRATION: ChineseClinicalTrialRegistry.org, ChiCTR2300076853. Registered on 22 October 2023.

Clinical characteristics of persistent or recurrent pneumonia combined with airway malacia in children.

OBJECTIVE: The aim of this study is to investigate the clinical characteristics and pathogens involved in persistent or recurrent pneumonia combined with airway malacia in children. METHODS: We retrospectively reviewed the information of children hospitalised with persistent or recurrent pneumonia, including clinical presentations, laboratory examination results and pathogens. RESULTS: A total of 554 patients were admitted, 285 (51.44%) of whom were found to have airway malacia. There were 78 (27.37%), 166 (58.25%) and 41 (14.39%) patients with mild, moderate and severe malacia, respectively. Patients with airway malacia were younger than those without malacia (6.0 vs. 12.0 months, p < 0.01) and were more likely to present with wheezing (75.07%), fever (34.39%), dyspnoea (28.77%), cyanosis (13.68%) and wheezing in the lungs (78.95%). The incidence of preterm delivery, oxygen therapy, paediatric intensive care unit (PICU) admission and mechanical ventilation was higher, and the hospital stay (11.0 vs. 10.0 days, p = 0.04) was longer in these patients than in those without malacia. Patients with severe airway malacia were more likely to undergo oxygen therapy, PICU admission, mechanical ventilation and have multiple malacia than were those with mild or moderate malacia. Mycoplasma pneumoniae (30.18%) was the most common pathogen. CONCLUSION: Severe airway malacia likely aggravates conditions combined with pneumonia. The proportion of multisite malacia was greater in severe airway malacia patients.

Microbial aetiology of community-acquired pneumonia in hospitalised adults: A prospective study utilising comprehensive molecular testing.

OBJECTIVES: This study aimed to describe the microbial aetiology of community-acquired pneumonia (CAP) in adults admitted to a tertiary care hospital and assess the impact of syndromic polymerase chain reaction (PCR) panels on pathogen detection. METHODS: Conducted at Haukeland University Hospital, Norway, from September 2020 to April 2023, this prospective study enrolled adults with suspected CAP. We analysed lower respiratory tract samples using both standard-of-care tests and the BIOFIRE® FILMARRAY® Pneumonia Plus Panel (FAP plus). The added value of FAP Plus in enhancing the detection of clinically relevant pathogens, alongside standard-of-care diagnostics, was assessed. RESULTS: Of the 3238 patients screened, 640 met the inclusion criteria, with 384 confirmed to have CAP at discharge. In these patients, pathogens with proven or probable clinical significance were identified in 312 (81.3%) patients. Haemophilus influenzae was the most prevalent pathogen, found in 118 patients (30.7%), followed by SARS-CoV-2 in 74 (19.3%), and Streptococcus pneumoniae in 64 (16.7%). Respiratory viruses were detected in 186 (48.4%) patients. The use of FAP plus improved the pathogen detection rate from 62.8% with standard-of-care methods to 81.3%. CONCLUSIONS: Pathogens were identified in 81% of CAP patients, with Haemophilus influenzae and respiratory viruses being the most frequently detected pathogens. The addition of the FAP plus panel, markedly improved pathogen detection rates compared to standard-of-care diagnostics alone.

Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD.

INTRODUCTION: Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention. METHODS: We evaluated the associations of common adult infections (herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses), and vaccinations against shingles and pneumonia, with the risks of AD and other dementias in a pseudorandomized sample of the Health and Retirement Study (HRS). RESULTS: Shingles, pneumonia and mycoses, diagnosed between ages 65 and 75, were all associated with significantly increased risk of AD later in life, by 16 %-42 %. Pneumococcal and shingles vaccines administered between ages 65-75 were both associated with a significantly lower risk of AD, by 15 %-21 %. These effects became less pronounced when AD was combined with other dementias. DISCUSSION: Our findings suggest that both the pneumococcal polysaccharide vaccine and the live attenuated zoster vaccine can offer significant protection against AD. It remains to be determined if non-live shingles vaccine has a similar beneficial effect on AD. This study also found significant associations of various infections with the risk of AD, but not with the risks of other dementias. This indicates that vulnerability to infections may play a more significant role in AD than in other types of dementia, which warrants further investigation.

Antibacterial peptide Reg4 ameliorates Pseudomonas aeruginosa-induced pulmonary inflammation and fibrosis.

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative facultative anaerobe that has become an important cause of severe infections in humans, particularly in patients with cystic fibrosis. The development of efficacious methods or mendicants against P. aeruginosa is still needed. We previously reported that regenerating islet-derived family member 4 (Reg4) has bactericidal activity against Salmonella Typhimurium, a Gram-negative flagellated bacterium. We herein explore whether Reg4 has bactericidal activity against P. aeruginosa. In the P. aeruginosa PAO1-chronic infection model, Reg4 significantly inhibits the colonization of PAO1 in the lung and subsequently ameliorates pulmonary inflammation and fibrosis. Reg4 recombinant protein suppresses the growth motility and biofilm formation capability of PAO1 in vitro. Mechanistically, Reg4 not only exerts bactericidal action via direct binding to the P. aeruginosa cell wall but also enhances the phagocytosis of alveolar macrophages in the host. Taken together, our study demonstrates that Reg4 may provide protection against P. aeruginosa-induced pulmonary inflammation and fibrosis via its antibacterial activity.IMPORTANCEChronic lung infection with Pseudomonas aeruginosa is a leading cause of morbidity and mortality in patients with cystic fibrosis. Due to the antibiotic resistance of Pseudomonas aeruginosa, antimicrobial peptides appear to be a potential alternative to combat its infection. In this study, we report an antimicrobial peptide, regenerating islet-derived 4 (Reg4), that showed killing activity against clinical strains of Pseudomonas aeruginosa PAO1 and ameliorated PAO1-induced pulmonary inflammation and fibrosis. Experimental data also showed Reg4 directly bound to the bacterial cell membrane and enhanced the phagocytosis of host alveolar macrophages. Our presented study will be a helpful resource in searching for novel antimicrobial peptides that could have the potential to replace conventional antibiotics.

P. aeruginosa tRNA-fMet halves secreted in outer membrane vesicles suppress lung inflammation in cystic fibrosis.

Although tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of Pseudomonas aeruginosa (P. aeruginosa) in the lungs is only modestly reduced by tobramycin; hence, the mechanism whereby tobramycin improves lung function is not completely understood. Here, we demonstrate that tobramycin increases 5' tRNA-fMet halves in outer membrane vesicles (OMVs) secreted by laboratory and CF clinical isolates of P. aeruginosa. The 5' tRNA-fMet halves are transferred from OMVs into primary CF human bronchial epithelial cells (CF-HBEC), decreasing OMV-induced IL-8 and IP-10 secretion. In mouse lungs, increased expression of the 5' tRNA-fMet halves in OMVs attenuated KC (murine homolog of IL-8) secretion and neutrophil recruitment. Furthermore, there was less IL-8 and neutrophils in bronchoalveolar lavage fluid isolated from pwCF during the period of exposure to tobramycin versus the period off tobramycin. In conclusion, we have shown in mice and in vitro studies on CF-HBEC that tobramycin reduces inflammation by increasing 5' tRNA-fMet halves in OMVs that are delivered to CF-HBEC and reduce IL-8 and neutrophilic airway inflammation. This effect is predicted to improve lung function in pwCF receiving tobramycin for P. aeruginosa infection.NEW & NOTEWORTHY The experiments in this report identify a novel mechanism, whereby tobramycin reduces inflammation in two models of CF. Tobramycin increased the secretion of tRNA-fMet halves in OMVs secreted by P. aeruginosa, which reduced the OMV-LPS-induced inflammatory response in primary cultures of CF-HBEC and in mouse lung, an effect predicted to reduce lung damage in pwCF.

Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection.

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.