Search

Although most countries recommend amoxicillin for paediatric pneumonia, there is a long tradition of treatment with penicillin V (PcV) in Sweden, thus not empirically covering Haemophilus influenzae. There are, however, large regional differences in treatment practice. The aim was to compare clinical outcomes (treatment failure and severe complications), in children aged 1–59 months treated with PcV vs. amoxicillin for pneumonia. This population-based emulated target trial included all children born in Sweden between 2001 and 2021, using national health, sociodemographic, and population registers. All pneumonia cases from hospitals and paediatric outpatient clinics in children aged 1–59 months treated as outpatients with PcV or amoxicillin between July 2005 and December 2021, were identified. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for treatment failure (newly dispensed antibiotic prescription or pneumonia-associated hospitalization day 1–14) and severe complications (lung complications, an invasive bacterial disease, admission to intensive care unit or death day 1–28) were calculated with logistic regression analysis. PcV was prescribed in 14 766 cases and amoxicillin in 10 566. Treatment failure occurred in 7.7% with PcV vs. 4.7% with amoxicillin, aOR 1.76 (95% CI: 1.54–2.00). Severe complications were rare, with no significant difference between PcV and amoxicillin (0.3% vs. 0.2%, aOR 0.96, 95% CI: 0.53–1.73). Sensitivity and interaction analyses showed consistent results. PcV treatment compared with amoxicillin, was associated with an increased risk for treatment failure but not for severe complications. The absolute risks for adverse outcomes were low in both groups suggesting a minor role of H. influenzae in paediatric pneumonia. [ABSTRACT FROM AUTHOR]

Background: Haemophilus influenzae is prevalent within the airways of persons with cystic fibrosis (pwCF). H. influenzae is often associated with pulmonary exacerbations (PEx) in pediatric cohorts, but in adults, studies have yielded conflicting reports around the impact(s) on clinical outcomes such as lung function decline. Accordingly, we sought to discern the prevalence, natural history, and clinical impact of H. influenzae in adult pwCF. Methods: This single-centre retrospective cohort study reviewed all adult pwCF with H. influenzae sputum cultures between 2002 and 2016. From this cohort, persistently infected subjects (defined as: ≥2 samples with the same pulsotype and > 50% sputum culture-positive for H. influenzae in each year) were matched (1:2) to controls without H. influenzae. Demographic and clinical status (baseline health or during periods of PEx) were obtained at each visit that H. influenzae was cultured. Yearly biobank isolates were typed using pulsed-field gel electrophoresis (PFGE) to assess relatedness. Results: Over the study period, 30% (n = 70/240) of pwCF were culture positive for H. influenzae, of which 38 (54%) were culture-positive on multiple occasions and 12 (17%) had persistent infection. One hundred and thirty-seven isolates underwent PFGE, with 94 unique pulsotypes identified. Two (1.5%) were serotype f with the rest non-typeable (98.5%). H. influenzae isolation was associated with an increased risk of PEx (RR = 1.61 [1.14–2.27], p = 0.006), however, this association was lost when we excluded those who irregularly produced sputum (i.e. only during a PEx). Annual lung function decline did not differ across cohorts. Conclusions: Isolation of H. influenzae was common amongst adult pwCF but often transient. H. influenzae infection was not associated with acute PEx or chronic lung function decline. [ABSTRACT FROM AUTHOR]

This research comprehensively investigates the epidemiological features and pathogen profile of acute respiratory infections (ARI) in Shihezi City, Xinjiang. A pivotal aspect of this study is the construction of a Bayes discriminant function for principal pathogen infections. This innovative methodology aims to furnish a robust scientific basis for the prevention and clinical management of ARI, potentially guiding more effective strategies in both public health and clinical settings. We compiled and examined data from January 2020 to June 2023, pertaining to patients admitted with acute respiratory infections at the First Affiliated Hospital of Shihezi University. This investigation focused on discerning patterns in epidemiology and pathogen etiology. Among 2110 cases of acute respiratory infections (ARI), 1736 underwent pathogenetic testing. Of these, 595 cases tested positive for at least one pathogen, marking a positivity rate of 34.27%. Viral detections, at a rate of 27.47%, were notably higher than bacterial detections, which stood at 6.51%. The most prevalent viruses identified were Human respiratory syncytial virus (hRSV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), and Human adenovirus (HAdV), while the dominant bacterial pathogens included Klebsiella pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Co‐infections were observed in 76 cases, accounting for 12.77% of positive diagnoses, predominantly involving hRSV in conjunction with other pathogens. In cases of acute bronchiolitis, hRSV was the most frequent pathogen, contributing to 23.10% of such cases. Similarly, in severe pneumonia cases, SARS‐CoV‐2 was predominant, accounting for 25.4% of these infections. The group with bacterial positivity exhibited elevated levels of C‐reactive protein (CRP, 19.17 mg/L) and neutrophilic granulocyte percentage (NE%, 54.7%). The Bayes discriminant function demonstrated an initial validation accuracy of 74.9% and a cross‐validation accuracy of 63.7%. The study underscores that hRSV, SARS‐CoV‐2, and HAdV are the primary pathogens in acute respiratory infections in the Shihezi region. Pathogen susceptibility exhibits variation across different age groups, with a higher pathogen detection rate in children compared to adults. The Bayes discriminant function shows significant promise in the classification and diagnosis of major pathogenic infections. [ABSTRACT FROM AUTHOR]

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS). Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted. Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles. Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility. [ABSTRACT FROM AUTHOR]

Aim: To examine how reduced iron content and added bovine lactoferrin in infant formula affect the antibody response following routine immunisation. Methods: In this randomised controlled trial, 180 Swedish formula‐fed infants received, from 6 weeks to 6 months of age, a 2 mg/L iron formula with (n = 72) or without (n = 72) bovine lactoferrin, or a control formula with 8 mg/L iron and no lactoferrin (n = 36). Another 72 infants were recruited as a breastfed reference. Serum immunoglobulin G (IgG) levels against Haemophilus influenzae type b (Hib), diphtheria and tetanus were assessed at four, six and 12 months of age. Results: With an equal gender distribution, 180 + 72 term infants were included with a mean age of 7.0 ± 0.7 weeks. At 12 months, infants fed low iron formula showed a significantly higher geometric mean Hib IgG (1.40 μg/mL [1.07–1.83]) compared to the control formula infants (0.67 μg/mL [0.42–1.07]). For all three vaccines, breastfed infants had significantly lower IgG levels at six and 12 months of age. Conclusion: Except for higher Hib IgG levels at 12 months in infants fed low iron formula, the interventions did not affect vaccine IgG response. Unexpectedly, breastfed infants had significantly lower vaccine IgG levels compared to formula‐fed infants. [ABSTRACT FROM AUTHOR]

Background/Objectives: The diagnosis of encephalitis is a challenging problem due to the heterogeneity of clinical presentations. The objective was to determine the etiology, clinical features, laboratory parameters, radiological findings, and in-hospital outcome of acute encephalitis syndrome (AES) cases in Myanmar. Methods: A prospective descriptive study was conducted at the Neuromedical Ward of Yangon General Hospital from March to August 2023. Eighty-one AES cases were enrolled, and cerebrospinal fluid (CSF) samples were collected. A Qiastat ME Panel was used to detect viral, bacterial, and fungal pathogens. Results: Seventeen out of eighty-one (21%) cases were non-encephalitis with alternative definite diagnosis. Among the remaining 64 encephalitis cases, the exact infectious and immune etiologies were identified in 31 of 64 cases (48.4%); 26 of these (83.9%) were due to infectious causes and 5 (16.1%) were immune encephalitis. Among the infectious causes, six Herpes Simplex Virus-1-, one bacteriologically confirmed and seven probable Mycobacterium tuberculosis-, three Haemophilus influenzae-, two Streptococcus pneumoniae-, one Streptococcus pyogenes-, one Varicella-Zoster Virus (Ramsay Hunt Syndrome with meningoencephalitis)-, and two Cryptococcus neoformans-infected patients and rare causes such as Listeria monocytogenes, Burkholdelria cepacia, Sphingomonas paucimobilis, and Aspergillus were identified. One case was a dual infection with Haemophilus influenzae and Cryptococcus neformans. Abnormal protein levels and CSF pleocytosis were significantly higher among bacterial causes (p < 0.05). In total, 6.45% (2/31) of encephalitis patients with identified causes and 12.12% (4/33) of those without an identified organism had poor outcome. Conclusions: Herpes encephalitis and tuberculous meningoencepalitis were the commonest. This study highlighted that molecular testing with a multidisciplinary approach is required to ensure the right treatment on time. [ABSTRACT FROM AUTHOR]

OBJECTIVES: American Indian and Alaska Native (AI/AN) infants historically experienced a disproportionate burden of invasive Haemophilus influenzae type b (Hib) disease, especially early in life. PedvaxHIB vaccine is preferentially recommended for AI/AN infants because it elicits protective antibody levels postdose 1. Vaxelis, a hexavalent vaccine that contains the same Hib conjugate as PedvaxHIB but at lower concentration, is recommended for US children, but postdose 1 Hib immunogenicity data are needed to inform whether a preferential recommendation should be made for AI/AN infants. METHODS: We conducted a phase IV randomized, open-label, noninferiority trial comparing postdose 1 immunogenicity of Vaxelis to PedvaxHIB in AI/AN infants. Participants were randomized to receive a primary series of PedvaxHIB or Vaxelis. Serum samples collected 30 days postdose 1 were tested for anti-Hib immunoglobulin G antibody by enzyme-linked immunosorbent assay. The anti-Hib immunoglobulin G geometric mean concentration (GMC) ratio (Vaxelis/PedvaxHIB) was estimated by constrained longitudinal data analysis. Noninferiority was defined a priori as the lower bound of the 95% confidence interval (CI) of the GMC ratio ≥0.67. RESULTS: A total of 327 of the 333 infants enrolled in the study were included in the per-protocol analysis. The postdose 1 anti-Hib GMC was 0.41 µg/mL (95% CI 0.33-0.52) in the Vaxelis group (n = 152) and 0.39 µg/mL (95% CI 0.31-0.50) in the PedvaxHIB group (n = 146). The constrained longitudinal data analysis GMC ratio was 1.03 (95% CI 0.76-1.39). CONCLUSIONS: Postdose 1 immunogenicity of Vaxelis was noninferior to PedvaxHIB. Our findings support the use of Vaxelis in AI/AN children, a population with elevated risk of Hib disease. [ABSTRACT FROM AUTHOR]

Evidence on serological responses to vaccination in children exposed to ustekinumab (UST) or vedolizumab (VDZ) in utero is lacking. This multicentre prospective study aimed to assess the impact of prenatal exposure to UST or VDZ due to maternal inflammatory bowel disease (IBD) on serological responses to vaccination and other immunological parameters in exposed children. Children aged ≥ 1 year who were exposed in utero to UST or VDZ and completed at least 1-year of mandatory vaccination were included. We assessed the serological response to vaccination (non-live: tetanus, diphtheria, and Haemophilus influenzae B; live: mumps, rubella, and measles), whole blood count, and immunoglobulin levels. The control group comprised unexposed children born to mothers without IBD. A total of 23 children (median age, 25 months) exposed to UST (n = 13) or VDZ (n = 10) and 10 controls (median age, 37 months) were included. The serological response to vaccination was comparable between the UST and VDZ groups and controls, with an adequate serological response rate of ≥ 80%. Only children exposed to UST showed a slightly reduced serological response to mumps (67% vs. 86% in controls), whereas all children exposed to VDZ showed an adequate response. The majority of the exposed children had normal levels of individual immunoglobulin classes, similar to the controls. No severe pathology was observed in any of the children. Conclusion: Despite the limited sample size, our findings suggest that in utero exposure to VDZ or UST does not significantly impair the vaccine response or broader immunological parameters in exposed children. What is known: • Treatment with anti-TNF inhibitors during pregnancy does not appear to affect serologic response to vaccination in exposed children. • Evidence on the efficacy of vaccination in children exposed to ustekinumab or vedolizumab in utero is almost lacking. What is new: • Our findings suggest that in utero exposure to ustekinumab or vedolizumab does not significantly affect the serological responses to common childhood non-live (tetanus, Haemophilus influenzae B, diphtheria) and live vaccines (measles, mumps, rubella). • No major adverse effects on overall immunological health were observed in children exposed in utero to ustekinumab or vedolizumab. [ABSTRACT FROM AUTHOR]

Introduction: H. influenzae carriage may evolve into respiratory or systemic infections. However, no surveillancesystem is in place in Belgium to monitor carriage strains. Material and Methods: This study provides a detailed description of H. influenzae strains isolated from both carriage and lower respiratory infections, collected during a six-month national surveillance. Subsequently, a comparison is conducted with invasive isolates collected during the same period at the National Reference Centre (NRC). Results and discussion: From November 2021 to April 2022, 39 clinical laboratories collected 142 and 210 strains of H. influenzae from carriage and infection, respectively, and 56 strains of blood were submitted to the NRC. In each group, the biotype II comprised more than 40%, followed by biotypes III and I. The majority of strains were non-typeable H. influenzae, with a notable increase in the number of encapsulated strains in the invasive group (14.3% vs. 1–2%). A beta-lactamase was identified in 18.5% and 12.5% of surveillance and invasive strains, respectively. Resistance to the amoxicillin-clavulanic acid combination accounted for 7% in the surveillance strains and 10.7% in invasive strains. The overall resistance to third-generation cephalosporins at 1.2% is consistent with rates observed in other European countries. Of particular significance is the identification of mutations in the ftsI gene in both carriage and infected strains, which are associated with high-level beta-lactam resistance. Conclusion: NRC must engage in regular and systematic monitoring of beta-lactam susceptibility of H. influenzae to guarantee safe empiric therapy in severe cases and identify potential transitions from low-level to high-level resistance in the future. [ABSTRACT FROM AUTHOR]

Background: Mixed infections can worsen disease symptoms. This study investigated the impact of mixed infections with viral and bacterial pathogens in patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Using the in-house multiplex PCR method, we tested 337 SARS-CoV-2 positive samples for co-infections with three bacterial and 14 other viral pathogens. Results: Between August 2021 and May 2022, 8% of 337 SARS-CoV-2-positive patients had bacterial co-infections, 5.6% had viral co-infections, and 1.4% had triple mixed infections. The most common causes of mixed infections were Haemophilus influenzae (5.93%) and respiratory syncytial virus (RSV) (1.18%). Children < 5 years old had more frequent co-infections than adults < 65 years old (20.8% vs. 16.4%), while adults showed a more severe clinical picture with a higher C-reactive protein (CRP) level (78.1 vs.16.2 mg/L; p = 0.033), a lower oxygen saturation (SpO2) (89.5 vs. 93.2%), and a longer hospital stay (8.1 vs. 3.1 days; p = 0.025) (mean levels). The risk of a fatal outcome was 41% in unvaccinated patients (p = 0.713), which increased by 2.66% with co-infection with two pathogens (p = 0.342) and by 26% with three pathogens (p = 0.005). Additionally, 50% of intensive care unit (ICU) patients had a triple infection, compared with only 1.3% in the inpatient unit (p = 0.0029). The risk of death and/or ICU admission was 12 times higher (p = 0.042) with an additional pathogen and increased by 95% (p = 0.003) with a third concomitant pathogen. Conclusions: Regular multiplex testing is important for prompt treatment and targeted antibiotic use. [ABSTRACT FROM AUTHOR]

Introduction: Bacterial meningitis is a major cause of death, with an approximate case fatality rate of 37% across all age groups in South Africa. This study aimed to describe the demographic and pathogen characteristics of incident meningitis in children aged <1 year in South Africa from 2014 through 2018, during a period when Haemophilus influenzae type b vaccine and pneumococcal conjugate vaccines (PCV) were both included in the expanded program on immunization (EPI). Methods: We conducted a cohort study of routine laboratory data in the National Health Laboratory Service Corporate Data Warehouse, which covers approximately 80% of the South African population. We defined a case of laboratory-confirmed bacterial meningitis as any person aged <1 year with meningitis diagnosed by culture and identification of a pathogen documented as being a common cause of meningitis in CSF. The cause-specific incidence risks were calculated by dividing the number of positive specimens in each age group and year by the corresponding mid-year population for children under 1 year old and those in the post-neonatal period (≥ 28 days to 365 days old). For children under 28 days old, the annual numbers of registered livebirths were used. We used Poisson regression to compare the incidence of meningitis by year. Results: We identified 3575 (1.5%) cases of culture-confirmed bacterial meningitis from the 232,016 cerebrospinal fluid (CSF) specimens tested from 2014–2018. The highest number of cases were recorded in children aged <28 days (1873, 52.4%), male children (1800, 50.4%) as well as in the Gauteng Province (2014, 56.3%). Acinetobacter baumannii (14.9%), followed by Klebsiella pneumoniae (13.5%), and group B streptococcus (GBS) (10.7%), were the most common pathogens detected. Overall, A. baumannii had the highest incidence risk, occurring at 9.8 per 100,000 persons in children aged <1 year in 2018. Among neonates, A. baumannii peaked at 14.9 per 100,000 livebirths in 2018, while Streptococcus pneumoniae was most common in the post-neonatal period (≥ 28 days to 365 days old), peaking at 9.8 per 100,000 persons in 2014. There was an increase in the annual incidence of most pathogens over the study period. Conclusion: There was an increasing trend in the annual incidence of bacterial meningitis in infants caused by most pathogens, particularly A. baumannii, K. pneumoniae and GBS. In addition to increased uptake of vaccination, prevention measures to reduce nosocomial and mother-to-child transmission of bacteria could include antenatal screening for GBS in pregnant women, rigorous hygiene in the hospital environment as well as rational antibiotic use. [ABSTRACT FROM AUTHOR]

Invasive Haemophilus influenzae type b (Hib) disease is a serious bacterial infection that disproportionally affects American Indian and Alaska Native (AI/AN) populations. Hib vaccination with a monovalent Hib conjugate vaccine consisting of Hib capsular polysaccharide (polyribosylribitol phosphate [PRP]) conjugated to outer membrane protein complex of Neisseria meningitidis serogroup B, PRP-OMP (PedvaxHIB, Merck and Co., Inc.) has historically been preferred for AI/AN infants, who are at increased risk for invasive Hib disease, because it provides substantial protection after the first dose. On June 26, 2024, CDC's Advisory Committee on Immunization Practices (ACIP) recommended that a hexavalent, combined diphtheria and tetanus toxoids and acellular pertussis (DTaP), inactivated poliovirus (IPV), Hib conjugate, and hepatitis B (HepB) vaccine, DTaP-IPV-Hib-HepB (Vaxelis, MSP Vaccine Company) should be included with monovalent PRP-OMP in the preferential recommendation for AI/AN infants because of the PRP-OMP Hib component. A primary Hib vaccination series consisting of either 1) monovalent PRP-OMP (2-dose series at ages 2 and 4 months) or 2) DTaP-IPV-Hib-HepB (3-dose series at ages 2, 4, and 6 months) is preferred for AI/AN infants. DTaP-IPV-Hib-HepB is only indicated for use in infants at ages 2, 4, and 6 months and should not be used for the booster doses of Hib, DTaP, or IPV vaccines. For the booster dose of Hib vaccine, no vaccine formulation is preferred for AI/AN children; any Hib vaccine (except DTaP-IPV-Hib-HepB) should be used. This report summarizes evidence considered for these recommendations and provides clinical guidance for the use of Hib-containing vaccines among AI/AN infants and children. [ABSTRACT FROM AUTHOR]

Background: Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α‐diversity microbiome. Methods: Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α‐diversity of mild‐moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS). Findings: Fifty‐one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF‐κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6‐transignalling signature and neutrophil activation. Conclusion: We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate respiratory syncytial virus (RSV) infections in cases followed in the pediatric intensive care unit (PICU). Materials and Methods: The study was designed as a prospective cohort in 6 PICUs. There were 3 groups: only RSV (+), RSV (v+) who were positive for another viral agent(s) in addition to RSV, and RSV (b+) who were positive for a bacterial agent(s) in addition to RSV. Results: A total of 119 cases were included in the study, 67 (56.3%) of whom were male. The RSV (+) group had a lower pH compared to the other groups and a higher rate of acute bronc hiolitis/bronchitis diagnoses compared to the RSV (v+) group. The RSV (v+) group had higher bicarbonate levels, higher creatinine levels, longer hospital stays, and higher Pediatric Risk of Mortality-3 scores (PRISM-3) compared to the RSV (+) group. Cases with RSV (b+) were younger and also had lower body weight compared to the other groups. Furthermore, the RSV (b+) group had higher C-reactive protein and Procalcitonin (PCT) levels and higher rates of High Flow Nasal Cannula-Oxygen Therapy (HFNC-OT) use. Multiple linear regression analysis revealed that PRISM-3 score, PCT levels, Pediatric Acute Respiratory Distress Syndrome diagnoses, inhaled steroid use, chronic illness status, and heart rate on admission were associated with the length of stay in the PICU. Conclusion: High flow nasal cannula-oxygen therapy continues to be the most frequently preferred respiratory support method in RSV infections. Viral infections accompanying RSV can increase the severity of the disease. [ABSTRACT FROM AUTHOR]

Community‐acquired necrotizing pneumonia is a rare but potentially fatal infection, mainly caused by specific pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. Escherichia coli is extremely rare as a pathogen for community‐acquired necrotizing pneumonia, typically accompanied with bloodstream infection. Here, we report an unusual case of a 60‐year‐old man with uncontrolled diabetes mellitus and no bloodstream infections, who had severe necrotizing E. coli pneumonia leading to massive hemoptysis and death. Clinicians should be aware of this pathogen in respiratory infections, as it requires immediate pathogen detection and usually aggressive antibiotic treatment. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to explore the prevalence of macrolide resistance and the underlying resistance mechanisms in Haemophilus influenzae (n  = 2556) and Haemophilus parainfluenzae (n  = 510) collected between 2018 and 2021 from Bellvitge University Hospital, Spain. Methods Antimicrobial susceptibility was tested by microdilution. Whole-genome sequencing was performed using Illumina MiSeq and Oxford Nanopore technologies, and sequences were examined for macrolide resistance determinants and mobile genetic structures. Results Macrolide resistance was detected in 67 H. influenzae (2.6%) and 52 (10.2%) H. parainfluenzae strains and associated with resistance to other antimicrobials (co-trimoxazole, chloramphenicol, tetracycline). Differences in macrolide resistance existed between the two species. Acquired resistance genes were more prevalent in H. parainfluenzae (35/52; 67.3%) than in H. influenzae (12/67; 17.9%). Gene mutations and amino acid substitutions were more common in H. influenzae (57/67; 85%) than in H. parainfluenzae (16/52; 30.8%). Substitutions in L22 and in 23S rRNA were only detected in H. influenzae (34.3% and 29.0%, respectively), while substitutions in L4 and AcrAB/AcrR were observed in both species. The MEGA element was identified in 35 (67.3%) H. parainfluenzae strains, five located in an integrative and conjugative element (ICE); by contrast, 11 (16.4%) H. influenzae strains contained the MEGA element (all in an ICE). A new ICE HpaHUB8 was described in H. parainfluenzae. Conclusions Macrolide resistance was higher in H. parainfluenzae than in H. influenzae , with differences in the underlying mechanisms. H. parainfluenzae exhibits co-resistance to other antimicrobials, often leading to an extensively drug-resistant phenotype. This highlights the importance of conducting antimicrobial resistance surveillance. [ABSTRACT FROM AUTHOR]

Objective: In a previous study we have shown that, in the presence of interleukin (IL)-33, repeated, per-nasal challenge of murine airways with Streptococcus pneumoniae (S. pneumoniae) organisms induces human asthma-like airways inflammation. It is not clear, however, whether this effect is unique or manifest in response to other common respiratory pathogens.Methods: To explore this, airways of BALB/c mice were repeatedly challenged per-nasally with formaldehyde-inactivated bacterial bodies in the presence or absence of murine recombinant IL-33. Serum concentrations of S.pneumoniae, Moraxella catarrhalis (M.catarrhalis) and Haemophilus influenzae (H.influenzae) lysates-specific IgE were measured in patients with asthma and control subjects.Results: We showed that in the presence of IL-33, repeated, per-nasal airways exposure to the bodies of these bacteria induced airways hyperresponsiveness (AHR) in the experimental mice. This was accompanied by cellular infiltration into bronchoalveolar lavage fluid (BALF), eosinophilic infiltration and mucous hypertrophy of the lung tissue, with elevated local expression of some type 2 cytokines and elevated, specific IgG and IgE in the serum. The precise characteristics of the inflammation evoked by exposure to each bacterial species were distinguishable.Conclusions: These results suggest that in the certain circumstances, inhaled or commensal bacterial body antigens of both Gram-positive (S. pneumoniae) and Gram-negative (M. catarrhalis and H. influenzae) respiratory tract bacteria may initiate type 2 inflammation typical of asthma in the airways. In addition, we demonstrated that human asthmatic patients manifest elevated serum concentrations of M.catarrhalis- and H.influenzae-specific IgE. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Haemophilus influenzae causes life-threatening invasive diseases such as septicaemia and meningitis. Reports on circulating H. influenzae causing invasive disease in lower-middle income settings, including Indonesia, are lacking. This study describes the serotype distributions and whole-genome sequence (WGS) data of H. influenzae isolated from hospitalized patients at Soetomo Hospital, Surabaya, Indonesia. Methods H. influenzae isolates were isolated from blood and pleural fluid specimens and identified using culture-based and molecular methods, followed by serotyping and WGS using RT‒PCR and Illumina MiSeq, respectively. Sequencing reads were assembled, and further analyses were undertaken to determine the genomic content and reconstruct the phylogeny. A second dataset consisting of publicly available H. influenzae genomes was curated to conduct phylogenetic analyses of isolates in this study in the context of globally circulating isolates. Results Ten H. influenzae isolates from hospitalized patients were collected, and septicaemia was the most common diagnosis (n=8). RT‒PCR and WGS were performed to determine whether all the isolates were nontypeable H. influenzae (NTHi). There were four newly identified STs distributed across the two main clusters. A total of 91 out of 126 virulence factor (VF)-related genes in Haemophilus sp. were detected in at least one isolate. Further evaluation incorporating a global collection of H. influenzae genomes confirmed the diverse population structure of NTHi in this study. Conclusion This study showed that all H. influenzae recovered from invasive disease patients were nonvaccine-preventable NTHi isolates. The inclusion of WGS revealed four novel STs and the possession of key VF-associated genes.

Rapid identification of causative bacteria in treatment of acute otitis media (AOM) is of paramount importance for appropriate antibiotic use. This prospective observational study was conducted in 15 hospitals and clinics in Japan between 2018 and 2020. A new rapid antigen test kit (AOS-116), which simultaneously detects antigens for Streptococcus pneumoniae (Sp) and Haemophilus influenzae (Hi), was applied for middle ear fluids (MEFs) and nasopharyngeal secretions (NPSs) in patients with moderate to severe AOM. We investigated relationship between the results of rapid test, severity at initial visit, and clinical course. Regarding performance accuracy based on culture results, AOS-116 showed 1) high (>80%) sensitivity, specificity, and negative predictive value (NPV) in MEFs for both antigens, 2) high sensitivity, specificity, and positive predictive value (PPV) in NPSs for Hi antigen, and 3) high specificity, and PPV in NPSs for Sp antigen. Regarding predictive value of nasopharyngeal culture and antigen detection for causative middle ear pathogens, similar results were observed between AOS-116 and culture, which was characterized with high sensitivity and NPV for both pathogens. MEFs/NPSs positive for Hi antigen were significantly associated with eardrum findings, and severity. MEFs/NPSs positive for pneumococcal antigen were significantly associated with severity of otalgia, fever, and otorrhea. Among patients with prior antimicrobial treatment, improvement tended to be slower in cases positive for Hi than in cases negative. The rapid antigen detection test is useful as a decision-making tool for prescribing antimicrobial agents and may play an important role in promoting appropriate antimicrobial use. [ABSTRACT FROM AUTHOR]

Abstract Background Haemophilus influenzae community-acquired pneumonia (CAP) is common, and it is equally common to Streptococcus pneumoniae in some settings. The purpose of this study was to provide additional data on patients affected by H. influenzae CAP and their outcomes. Methods Streptococcus pneumoniae-caused CAP (111 cases) was compared to CAP with H. influenzae (53 cases). Patients were adults (≥ 18 years) from the prospective study “Etiology of community acquired pneumonia in Sweden” (ECAPS), which was established during the years 2016–2018. Results Cases with H. influenzae CAP were significantly older compared to S. pneumoniae CAP (median 77 vs 70 years, p = 0.037) albeit similar comorbidities. Haemophilus influenzae was generally absent in the bloodstream compared to S. pneumoniae (18% vs 2%, p = 0.01) but clinical presentations were comparable. Only a minority of patients, 34% with H. influenzae and 41% with S. pneumoniae CAP had underlying lung disease. Conclusion In the light of childhood immunization campaigns against S. pneumoniae and the increasing numbers of pneumococcal vaccinations among the elderly, coupled with an aging population, the incidence of CAP caused by H. influenzae may increase. Further research is needed to understand the impact of H. influenzae CAP and to a development of a vaccine against this emerging microbe.

We recently characterized the competitive inhibition of cyclic AMP (cAMP) on three periplasmic acid phosphatases, AphAHi, NadNHi, and eP4 (HelHi), in Haemophilus influenzae Rd KW20. This inhibitory effect is vital for orchestrating the nutritional growth and competence development in KW20. Initially discovered in Escherichia coli, the function of AphA remains however obscure. This study investigates the regulation of E. coli aphA expression under nutrient starvation conditions. Using transcriptional reporters with truncated aphA promoter sequences, we found that starvations of carbon and phosphate, but not amino acid, stimulated aphA expression through distinct promoter regions. Deletions of crp or cyaA abolished aphA expression, confirming their crucial roles. Conversely, CytR deletion increased aphA expression, suggesting CytR's role as a repressor of aphA expression. Additionally, we extended the study of three other second messengers, i.e., cyclic GMP, cyclic UMP, and cyclic CMP, each sharing structural similarities with cAMP. Notably, cGMP competitively inhibits AphAHi's acid phosphatase activity akin to cAMP. In contrast, both cUMP and cCMP stimulate AphAHi's phosphatase activity in a concentration dependent manner. Collectively, these data imply a complicated connection between nucleotide metabolism, AphA, cyclic purine and pyrimidine nucleotides in bacterial nutrient uptake and natural competence.

Abstract The COVID-19 pandemic has altered the infection landscape for many pathogens. This retrospective study aimed to compare Haemophilus influenzae (H. influenzae) infections in pediatric CAP patients hospitalized before (2018–2019) and during (2020–2022) the COVID-19 pandemic. We analyzed the clinical epidemiology and antimicrobial resistance (AMR) patterns of H. influenzae from a tertiary hospital in southwest China. A total of 986 pediatric CAP patients with H. influenzae-associated infections were included. Compared to 2018, the positivity rate increased in 2019 but dropped significantly in 2020. Although it rose in the following 2 years, the rate in 2022 remained significantly lower than in 2019. Patients’ age during the pandemic was significantly higher than in 2018 and 2019, while gender composition remained similar across both periods. Notably, there were significant changes in co-infections with several respiratory pathogens during the pandemic. Resistance rates of H. influenzae isolates to antibiotics varied, with the highest resistance observed for ampicillin (85.9%) and the lowest for cefotaxime (0.0%). Resistance profiles to various antibiotics underwent dramatic changes during the COVID-19 pandemic. Resistance to amoxicillin-clavulanate, cefaclor, cefuroxime, trimethoprim-sulfamethoxazole, and the proportion of multi-drug resistant (MDR) isolates significantly decreased. Additionally, MDR isolates, alongside isolates resistant to specific drugs, were notably prevalent in ampicillin-resistant and β-lactamase-positive isolates. The number of pediatric CAP patients, H. influenzae infections, and isolates resistant to certain antibiotics exhibited seasonal patterns, peaking in the winter of 2018 and 2019. During the COVID-19 pandemic, sharp decreases were observed in February 2020, and there was no resurgence in December 2022. These findings indicate that the COVID-19 pandemic has significantly altered the infection spectrum of H. influenzae in pediatric CAP patients, as evidenced by shifts in positivity rate, demographic characteristics, respiratory co-infections, AMR patterns, and seasonal trends.

Influenza-like illness (ILI) patients co-detected with respiratory pathogens exhibit poorer health outcomes than those with single infections. To address the paucity of knowledge concerning the incidence of concurrent respiratory pathogens, their relationships, and the clinical differences between patients detected with single and multiple pathogens, we performed an in-depth characterization of the oropharyngeal samples of primary care patients collected in Genoa (Northwest Italy), during winter seasons 2018/19–2019/20. The apriori algorithm was employed to evaluate the incidence of viral, bacterial, and viral-bacterial pairs during the study period. The grade of correlation between pathogens was investigated using the Phi coefficient. Factors associated with viral, bacterial or viral-bacterial co-detection were assessed using logistic regression. The most frequently identified pathogens included influenza A, rhinovirus, Haemophilus influenzae and Streptococcus pneumoniae. The highest correlations were found between bacterial-bacterial and viral-bacterial pairs, such as Haemophilus influenzae-Streptococcus pneumoniae, adenovirus-Haemophilus influenzae, adenovirus-Streptococcus pneumoniae, RSV-A-Bordetella pertussis, and influenza B Victoria-Bordetella parapertussis. Viruses were detected together at significantly lower rates. Notably, rhinovirus, influenza, and RSV exhibited significant negative correlations with each other. Co-detection was more prevalent in children aged < 4, and cough was shown to be a reliable indicator of viral co-detection. Given the evolving epidemiological landscape following the COVID-19 pandemic, future research utilizing the methodology described here, while considering the circulation of SARS-CoV-2, could further enrich the understanding of concurrent respiratory pathogens. [ABSTRACT FROM AUTHOR]

Glycoconjugate vaccines are based on chemical conjugation of pathogen‐associated carbohydrates with immunogenic carrier proteins and are considered a very cost‐effective way to prevent infections. Most of the licensed glycoconjugate vaccines are composed of saccharide antigens extracted from bacterial sources. However, synthetic oligosaccharide antigens have become a promising alternative to natural polysaccharides with the advantage of being well‐defined structures providing homogeneous conjugates. Haemophilus influenzae (Hi) is responsible for a number of severe diseases. In recent years, an increasing rate of invasive infections caused by Hi serotype a (Hia) raised some concern, because no vaccine targeting Hia is currently available. The capsular polysaccharide (CPS) of Hia is constituted by phosphodiester‐linked 4‐β‐d‐glucose‐(1→4)‐d‐ribitol‐5‐(PO4→) repeating units and is the antigen for protein‐conjugated polysaccharide vaccines. To investigate the antigenic potential of the CPS from Hia, we synthesized related saccharide fragments containing up to five repeating units. Following the synthetic optimization of the needed disaccharide building blocks, they were assembled using the phosphoramidite approach for the installation of the phosphodiester linkages. The resulting CPS‐based Hia oligomers were conjugated to CRM197 carrier protein and evaluated in vivo for their immunogenic potential, showing that all glycoconjugates were capable of raising antibodies recognizing Hia synthetic fragments. [ABSTRACT FROM AUTHOR]

Background: Haemophilus influenzae community-acquired pneumonia (CAP) is common, and it is equally common to Streptococcus pneumoniae in some settings. The purpose of this study was to provide additional data on patients affected by H. influenzae CAP and their outcomes. Methods: Streptococcus pneumoniae-caused CAP (111 cases) was compared to CAP with H. influenzae (53 cases). Patients were adults (≥ 18 years) from the prospective study "Etiology of community acquired pneumonia in Sweden" (ECAPS), which was established during the years 2016–2018. Results: Cases with H. influenzae CAP were significantly older compared to S. pneumoniae CAP (median 77 vs 70 years, p = 0.037) albeit similar comorbidities. Haemophilus influenzae was generally absent in the bloodstream compared to S. pneumoniae (18% vs 2%, p = 0.01) but clinical presentations were comparable. Only a minority of patients, 34% with H. influenzae and 41% with S. pneumoniae CAP had underlying lung disease. Conclusion: In the light of childhood immunization campaigns against S. pneumoniae and the increasing numbers of pneumococcal vaccinations among the elderly, coupled with an aging population, the incidence of CAP caused by H. influenzae may increase. Further research is needed to understand the impact of H. influenzae CAP and to a development of a vaccine against this emerging microbe. [ABSTRACT FROM AUTHOR]

In May 2023, the Detroit Health Department was notified of four cases of invasive nontypeable Haemophilus influenzae (Hi) disease among students attending the same elementary school and grade, all with illness onsets within 7 days. Three patients were hospitalized, and one died. Most U.S. cases of invasive Hi disease are caused by nontypeable strains. No vaccines against nontypeable or non-type b Hi strains are currently available. Chemoprophylaxis is not typically recommended in response to nontypeable Hi cases; however, because of the high attack rate (four cases among 46 students; 8.7%), rifampin prophylaxis was recommended for household contacts of patients with confirmed cases and for all students and staff members in the school wing where confirmed cases occurred. Only 10.8% of students for whom chemoprophylaxis was recommended took it, highlighting gaps in understanding among caregivers and health care providers about persons for whom chemoprophylaxis was recommended. Public health authorities subsequently enhanced communication and education to the school community, improved coordination with health care partners, and established mass prophylaxis clinics at the school. This outbreak highlights the potential for nontypeable Hi to cause serious illness and outbreaks and the need for chemoprophylaxis guidance for nontypeable Hi disease. Achieving high chemoprophylaxis coverage requires education, communication, and coordination with community and health care partners. [ABSTRACT FROM AUTHOR]

Background Despite vaccination, influenza and otitis media (OM) remain leading causes of illness. We previously found that the human respiratory commensal Haemophilus haemolyticus prevents bacterial infection in vitro and that the related murine commensal Muribacter muris delays OM development in mice. The observation that M muris pretreatment reduced lung influenza titer and inflammation suggests that these bacteria could be exploited for protection against influenza/OM. Methods Safety and efficacy of intranasal H haemolyticus at 5 × 107 colony-forming units (CFU) was tested in female BALB/cARC mice using an influenza model and influenza-driven nontypeable Haemophilus influenzae (NTHi) OM model. Weight, symptoms, viral/bacterial levels, and immune responses were measured. Results Intranasal delivery of H haemolyticus was safe and reduced severity of influenza, with quicker recovery, reduced inflammation, and lower lung influenza virus titers (up to 8-fold decrease vs placebo; P ≤.01). Haemophilus haemolyticus reduced NTHi colonization density (day 5 median NTHi CFU/mL = 1.79 × 103 in treatment group vs 4.04 × 104 in placebo, P =.041; day 7 median NTHi CFU/mL = 28.18 vs 1.03 × 104; P =.028) and prevented OM (17% OM in treatment group, 83% in placebo group; P =.015). Conclusions Haemophilus haemolyticus has potential as a live biotherapeutic for prevention or early treatment of influenza and influenza-driven NTHi OM. Additional studies will deem whether these findings translate to humans and other respiratory infections. [ABSTRACT FROM AUTHOR]

Neutrophilic asthma, as corticosteroid resistant asthma, is clinically more severe than eosinophilic asthma. Therefore, the treatment of neutrophilic asthma has been a challenging. Reactive oxygen species (ROS) play a key role in the neutrophilic asthma. However, the direct use of antioxidant enzymes, such as catalase (CAT), is challenging due to the poor stability, short plasma half‐life, and the lack of effective drug delivery systems to pulmonary systems. In this work, a novel kind of nanogels for delivering CAT (CAT‐NGs) is synthesized, incorporating CAT with an antibacterial "protective film", as a modality for the treatment of neutrophilic asthma. Compared with free CAT, CAT‐NGs demonstrated superior enzyme activity and trypsin resistance, and exhibited outstanding anti‐inflammatory and antioxidant activities in vitro. Furthermore, CAT‐NGs showed significant inhibitory effects on nontypeable Haemophilus influenzae (NTHi), Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Additionally, nebulized inhalation of CAT‐NGs alleviated pulmonary inflammation in neutrophilic asthma mice. Mechanistically, the alleviation of neutrophilic asthma symptoms by CAT‐NGs is possibly associated with the clearance of ROS in the lung and the inhibition of the NLRP3 and NF‐κB pathways. Hence, the work have demonstrated the therapeutic potential of CAT‐NGs, offering new insights into the clinical treatment of neutrophilic asthma. [ABSTRACT FROM AUTHOR]

Background and Objective: COPD and bronchiectasis are common causes of morbidity, particularly around exacerbation. Colonisation with respiratory pathogens can increase the frequency and severity of exacerbations. However, bacterial and viral presence at exacerbation in people with airway colonisation has not been well studied. Methods: A 6‐month cohort study of participants (n = 30) with chronic bronchitis due to bronchiectasis (n = 26) and/or COPD (n = 13) and colonisation with Pseudomonas aeruginosa or Haemophilus influenzae was proven on two sputum cultures at exacerbation in the previous 12 months. Participants were provided self‐management education and collected sputum samples daily. Sputum samples at baseline (at least 14 days before or after an exacerbation) and at each exacerbation were examined for a panel of 34 respiratory pathogens using commercially available RT‐PCR kits and compared to results obtained using culture methods for the detection of bacteria. Results: Participants provided 29 baseline samples and 71 samples at exacerbation. In 17/29 baseline samples, RT‐PCR analysis confirmed the organism demonstrated by culture, while 12 samples showed a discrepancy from culture results. Most exacerbations (57.7%) were not associated with acquiring new bacteria or viruses, while 19.8% showed new bacteria, 15.7% new viruses and 7% both new viruses and bacteria. Conclusion: Over half of exacerbations were not associated with new organisms in this cohort of participants with chronic bronchitis and colonisation. However, 26.8% demonstrated a new bacterial species in sputum, which is relevant for antibiotic therapy. Baseline RT‐PCR and culture results were discordant in one‐third of participants. [ABSTRACT FROM AUTHOR]

Acute bacterial meningitis (ABM) is associated with severe morbidity and mortality. The most prevalent pathogens in community-acquired ABM are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Other pathogens may affect specific patient groups, such as newborns, older patients, or immunocompromised patients. It is well established that ABM is associated with elevated intracranial pressure (ICP). However, the role of ICP monitoring and management in the treatment of ABM has been poorly described.An electronic search was performed in four electronic databases: PubMed, Web of Science, Embase, and the Cochrane Library. The search strategy chosen for this review used the following terms: Intracranial Pressure AND (management OR monitoring) AND bacterial meningitis. The search yielded a total of 403 studies, of which 18 were selected for inclusion. Eighteen studies were finally included in this review. Only one study was a randomized controlled trial. All studies employed invasive ICP monitoring techniques, whereas some also relied on assessment of ICP-based on clinical and/or radiological observations. The most commonly used invasive tools were external ventricular drains, which were used both to monitor and treat elevated ICP. Results from the included studies revealed a clear association between elevated ICP and mortality, and possibly improved outcomes when invasive ICP monitoring and management were used. Finally, the review highlights the absence of clear standardized protocols for the monitoring and management of ICP in patients with ABM. This review provides an insight into the role of invasive ICP monitoring and ICP-based management in the treatment of ABM. Despite weak evidence certainty, the present literature points toward enhanced patient outcomes in ABM with the use of treatment strategies aiming to normalize ICP using continuous invasive monitoring and cerebrospinal fluid diversion techniques. Continued research is needed to define when and how to employ these strategies to best improve outcomes in ABM. [ABSTRACT FROM AUTHOR]

Objective: To investigate the pathogen distribution and clinical characteristics of acute community-acquired lower respiratory tract infections (CALRTIs). Methods: This was a retrospective study. The clinical data of 218 patients with CALRTIs admitted to Baoding No.1 Central Hospital from December 2021 to December 2022 were retrospectively collected and were divided into two groups according to the results of polymerase chain reaction(PCR) testing using a nasopharyngeal swab: streptococcus pneumoniae positive group(observation group) and non-streptococcus pneumoniae positive group(control group). Clinical symptoms, blood gas analysis indicators were compared between the two groups. Results: Haemophilus influenzae and Staphylococcus aureus, as well as virus and atypical pathogen infection, were the predominant pathogenic bacteria in both groups. No statistically significant differences were observed in the positive rates of sputum smear, sputum culture, respiratory virus detection and atypical pathogen detection between the two groups(P>0.05). However, the control group had a higher detection rate of gram-positive bacteria, gram-negative bacteria and Legionella pneumophila in sputum smears than the observation group, with a statistically significant difference(P<0.05). One death occurred in each group, with no significant difference in mortality and six in each group left the hospital or were transferred due to deterioration, with no significant difference in improved discharge rates. Conclusion: Acute community-acquired lower respiratory tract infections(CALRTIs) take bacteria, viruses and atypical pathogens as its leading pathogenic bacteria. In the treatment of patients with acute CALRTIs, early pathogenic examination should be performed to assist in guiding antibiotic therapy for rapid control, early recovery and ameliorated clinical outcomes. [ABSTRACT FROM AUTHOR]

Patients with cystic fibrosis (CF) are prone to developing life-threatening lung infections with a variety of pathogens that are difficult to eradicate, such as Burkholderia cepacia complex (Bcc), Hemophilus influenzae, Mycobacterium abscessus (Mab), Pseudomonas aeruginosa, and Staphylococcus aureus. These infections still remain an important issue, despite the therapy for CF having considerably improved in recent years. Moreover, prolonged exposure to antibiotics in combination favors the development and spread of multi-resistant bacteria; thus, the development of alternative strategies is crucial to counter antimicrobial resistance. In this context, phage therapy, i.e., the use of phages, viruses that specifically infect bacteria, has become a promising strategy. In this review, we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients. [ABSTRACT FROM AUTHOR]

The rapid and accurate diagnosis of meningitis is critical for preventing severe complications and fatalities. This study addresses the need for accessible diagnostics in the absence of specialized equipment by developing a novel diagnostic assay. The assay utilizes dual-priming isothermal amplification (DAMP) with unique internal primers to significantly reduce non-specificity. For fluorescence detection, the dye was selected among Brilliant Green, Thioflavin T, and dsGreen. Brilliant Green is preferred for this assay due to its availability, high fluorescence level, and optimal sample-to-background (S/B) ratio. The assay was developed for the detection of the primary causative agents of meningitis (Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae), and tested on clinical samples. The developed method demonstrated high specificity, no false positives, sensitivity comparable to that of loop-mediated isothermal amplification (LAMP), and a high S/B ratio. This versatile assay can be utilized as a standalone test or an integrated assay into point-of-care systems for rapid and reliable pathogen detection. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the pathogen epidemiology of community‐acquired pneumonia (CAP) among children in Southwest China before, during and after the COVID‐19 non‐pharmaceutical interventions (NPIs). Methods: Pathogen data of hospitalised children with CAP, including multiple direct immunofluorescence test for seven viruses, bacterial culture and polymerase chain reaction (PCR) for Mycoplasma pneumoniae, were analysed across three phases: Phase I (pre‐NPIs: 1 January 2019 to 31 December 2019), Phase II (NPI period: 1 January 2020 to 31 December 2020) and Phase III (post‐NPIs: 1 January 2023 to 31 December 2023). Results: A total of 7533 cases were enrolled, including 2444, 1642 and 3447 individuals in Phases I, II and III, respectively. M. pneumoniae predominated in Phases I and III (23.4% and 35.5%, respectively). In Phase II, respiratory syncytial virus (RSV) emerged as the primary pathogen (20.3%), whereas detection rates of influenza A virus (Flu A) and M. pneumoniae were at a low level (1.8% and 9.6%, respectively). In Phase III, both Flu A (15.8%) and M. pneumoniae epidemic rebounded, whereas RSV detection rate returned to Phase I level, and detection rates of Streptococcus pneumoniae and Haemophilus influenzae decreased significantly compared to those in Phase I. Detection rates of adenovirus and parainfluenza virus type 3 decreased phase by phase. Age‐stratified analysis and monthly variations supported the above findings. Seasonal patterns of multiple pathogens were disrupted during Phases II and III. Conclusions: COVID‐19 NPIs exhibited a distinct impact on CAP pathogen epidemic among children, with post‐NPIs increases observed in M. pneumoniae and Flu A prevalence. Continuous pathogen monitoring is crucial for effective prevention and control of paediatric CAP. [ABSTRACT FROM AUTHOR]

Asthma is a chronic and heterogeneous disease affecting the lungs and respiratory tract. In particular, the neutrophil subtype of asthma was described as persistent, more severe, and corticosteroid-resistant. Growing evidence suggested that nontypeable Haemophilus influenzae (NTHi) infection contributes to the development of neutrophilic asthma, exacerbating clinical symptoms and increasing the associated medical burden. In this work, arginine-grafted chitosan (CS-Arg) was ionically cross-linked with tris(2-carboxyethyl) phosphine (TCEP), and a highly-efficient antimicrobial agent, poly-ε-L-Lysine (ε-PLL), was incorporated to prepare ε-PLL/CS-Arg/TCEP (ECAT) composite nanogels. The results showed that ECAT nanogels exhibited highly effective inhibition against the proliferation of NTHi, Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). In addition, ECAT nanogels could effectively inhibit the formation of mucins aggregates in vitro , suggesting that the nanogel might have the potential to destroy mucin in respiratory disease. Furthermore, in the ovalbumin (OVA)/NTHi-induced Balb/c mice model of neutrophilic asthma, the number of neutrophils in the alveolar lavage fluid and the percentage of inflammatory cells in the blood were effectively reduced by exposure to tower nebulized administration of ECAT nanogels, and reversing airway hyperresponsiveness (AHR) and reducing inflammation in neutrophilic asthma mice. In conclusion, the construction of ECAT nanogels was a feasible anti-infective and anti-inflammatory therapeutic strategy, which demonstrated strong potential in the clinical treatment of neutrophilic asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

This study aimed to investigate LRTIs in cancer patients, focusing on pathogen distribution, and outcomes based on tumor types and antimicrobial treatments. The study included 110 cancer patients exhibiting symptoms of lower respiratory tract infections (LRTIs), consisting of 67 males and 43 females across a wide age range from under 1 year to over 60 years old. Exclusion of SARS-CoV-2 infection was conducted before admission. In addition to classical microbiological methods, fast-track detection using Multiplex Real-Time PCR was employed, utilizing the FTD-33 test kit. The findings revealed a diverse landscape of infections, notably Klebsiella pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Parainfluenza 3 and 4 viruses, rhinovirus, influenza A subtype H1N1pdm09, influenza B and C viruses, HCoV-229, HCoV-OC43, and HCoV-HKU1 were infrequently detected. Furthermore, the existence of mixed infection highlighted the complexity of disease conditions in cancer patients. An analysis of antimicrobial treatment highlighted significant variations in fatal outcomes for carbapenem and colistimethate sodium. It was concluded that mixed infections were commonly identified as potential causes of LRTIs among cancer patients, while viral infections were less frequently detected. It underscores the complexity of antimicrobial treatment outcomes. [ABSTRACT FROM AUTHOR]

Biofilms, aggregates of bacteria enclosed in a self-produced matrix, have been implicated in various pediatric respiratory infections, including acute otitis media (AOM), otitis media with effusion (OME), adenoiditis, protracted bacterial bronchitis, and pulmonary exacerbations in cystic fibrosis. These infections are prevalent in children and often associated with biofilm-producing pathogens, leading to recurrent and chronic conditions. Biofilms reduce antibiotic efficacy, contributing to treatment failure and disease persistence. This narrative review discusses biofilm production by respiratory pathogens such as Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. It examines their mechanisms of biofilm formation, antibiotic resistance, and the challenges they present in clinical treatment. Various antibiofilm strategies have shown promise in vitro and in animal studies, including the use of N-acetylcysteine, enzymes like dispersin B, and agents disrupting quorum sensing and biofilm matrix components. However, their clinical application, particularly in children, remains limited. Traditional treatments for biofilm-associated diseases have not significantly evolved, even with biofilm detection. The transition from experimental findings to clinical practice is complex and requires robust clinical trials and standardized biofilm detection protocols. Addressing biofilms in pediatric respiratory infections is crucial for improving treatment outcomes and managing recurrent and chronic diseases effectively. [ABSTRACT FROM AUTHOR]

Objective: To explore the underlying mechanisms the airway microbiome contributes to Acute Exacerbation of Chronic Obstructive Pulmonary Disease(AECOPD). Methods: We enrolled 31 AECOPD patients and 26 stable COPD patients, their sputum samples were collected for metagenomic and RNA sequencing, and then subjected to bioinformatic analyses. The expression of host genes was validated by Quantitative Real-time PCR(qPCR) using the same batch of specimens. Results: Our results indicated a higher expression of Rothia mucilaginosa (p=0.015) in the AECOPD group and Haemophilus influenzae(p=0.005) in the COPD group. The Different expressed genes(DEGs) detected were significantly enriched in "type I interferon signaling pathway"(p<0.001, q=0.001) in gene function annotation, and "Cytosolic DNA-sensing pathway"(p=0.002, q=0.024), "Toll-like receptor signaling pathway"(p=0.006, q=0.045), and "TNF signaling pathway"(p=0.006, q=0.045) in KEGG enrichment analysis. qPCR amplification experiment verified that the expression of OASL and IL6 increased significantly in the AECOPD group. Conclusion: Pulmonary bacteria dysbiosis may regulate the pathogenesis of AECOPD through innate immune system pathways like type I interferon signaling pathway and Toll-like receptor signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilus influenzae (HI) is an exceedingly rare cause of infective endocarditis (IE). Case Presentation/Methods: We present a case of a 90-year-old female diagnosed with HI-IE involving the native tricuspid valve in the absence of traditional risk factors for right-sided endocarditis. She was treated with a 5-week course of IV Ampicillin from negative cultures and suffered no complications. We also conducted a thorough literature review through PubMed and Google Scholar, which yielded a mere 15 reported cases of HI-IE. Results: Fourteen of the reported HI-IE cases included epidemiological data, showing no gender predominance. The mean age of the subjects was 39.5, with the mitral valve being the most implicated (64%) and tricuspid valve involvement being rare (21%). Conclusion: Native tricuspid valve IE is an uncommon entity, especially in the absence of IV drug use. Haemophilus influenzae is an extremely rare cause of IE, with a literature review showing merely 15 reported cases. This article cites the 16th case of HI-IE published in the literature. [ABSTRACT FROM AUTHOR]

Infections due to Haemophilus influnezae require prompt treatment using beta-lactam antibiotics. We used a collection of 81 isolates obtained between 1940 and 2001 from several countries. Whole genome sequencing showed the high heterogeneity of these isolates but allowed us to track the acquisition of beta-lactamase, which was first detected in 1980. Modifications of the ftsI gene encoding the penicillin-binding protein 3, PBP3, also involved in resistance to beta-lactams, appeared in 1991. These modifications (G490E, A502V, R517H, and N526K) were associated with resistance to amoxicillin that was not relieved by a beta-lactamase inhibitor (clavulanic acid), but the isolates retained susceptibility to third-generation cephalosporins (3GC). The modeling of the PBP3 structure suggested that these modifications may reduce the accessibility to the PBP3 active site. Other modifications appeared in 1998 and were associated with resistance to 3GC (S357N, M377I, S385T, and L389F). Modeling of the PBP3 structure suggested that they lie near the S379xN motif of the active site of PBP3. Overall resistance to amoxicillin was detected among 25 isolates (30.8%) of this collection. Resistance to sulfonamides was predicted by a genomic approach from the sequences of the folP gene (encoding the dihydropteroate synthase) due to difficulties in interpreting phenotypic anti-microbial testing and found in 13 isolates (16.0%). Our data suggest a slower spread of resistance to sulfonamides, which may be used for the treatment of H. influnezae infections. Genomic analysis may help in the prediction of antibiotic resistance, inform structure–function analysis, and guide the optimal use of antibiotics. [ABSTRACT FROM AUTHOR]

Acute respiratory tract infections are one of the leading causes of morbidity and mortality worldwide. More data are needed on circulating respiratory microorganisms in different geographical areas and ecosystems. We analyzed nasopharyngeal swabs from 500 febrile patients living in the Niakhar area (Senegal), using FTDTM multiplex qPCR and simplex qPCR to target a panel of 25 microorganisms. We detected at least one microorganism for 366/500 patients (73.2%), at least one virus for 193/500 (38.6%), and at least one bacterium for 324/500 (64.8%). The most frequently detected microorganisms were Streptococcus pneumoniae (36.8%), Haemophilus influenzae (35.8%), adenovirus (11.8%), influenza viruses (6.4%), rhinovirus (5.0%), SARS-CoV-2 (4.0%), and RSV (4.0%). The main microorganisms significantly associated with respiratory symptoms, with a p-value ≤ 0.05, were influenza virus (11.9% in patients with respiratory symptoms versus 2.9% in patients without), RSV (6.5% versus 2.6%), metapneumovirus (5.4% versus 1.3%), HPIVs (7.6% versus 1.0%), S. pneumoniae (51.9% versus 28.0%), and H. influenzae (54.6% versus 24.5%). Co-infections were significantly associated with respiratory symptoms (65.4% versus 32.9%). All the epidemiological data show a high level of circulation of respiratory pathogens among febrile patients, including those preventable by vaccination such as S. pneumoniae, raising the question of the serotypes currently circulating. Furthermore, the availability of affordable real-time etiological diagnostic tools would enable management to be adapted as effectively as possible. [ABSTRACT FROM AUTHOR]

Introduction Methodology Results Conclusion Allergic fungal rhinosinusitis (AFRS) is a severe phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP), characterised by localised and exaggerated type 2 inflammation. While fungal antigenic stimulation of unregulated Th2‐mediated inflammation is the core pathophysiological mechanism, the direct and synergistic role of bacteria in disease modification is a pervasive hypothesis. We set out to define the microenvironment of AFRS to elucidate virulent organisms that may be implicated in the pathophysiology of AFRS.We undertook a cross‐sectional study of AFRS patients and non‐fungal CRSwNP patients. Demographics, disease severity, culture and microbiome sequences were analysed. Multimodality microbiome sequencing included short‐read next‐generation sequencing (NGS) on the Illumina Miseq (16S rRNA and ITS) and full‐length 16S rRNA sequencing on the Oxford Nanopore Technologies GridION (ONT).Thirty‐two AFRS and 29 non‐fungal CRSwNP patients (NF) were included in this study. Staphylococcus aureus was the dominant organism cultured and sequenced in both AFRS and NF groups (AFRS 27.54%; NF 18.04%; p = .07). Streptococcus pneumoniae (AFRS 12.31%; NF 0.98%; p = .03) and Haemophilus influenzae (AFRS 15.03%; NF 0.24%; p = .005) were significantly more abundant in AFRS. Bacterial diversity (Shannon's index) was considerably lower in AFRS relative to NF (AFRS 0.6; NF 1.0, p = .008). Aspergillus was the most cultured fungus in AFRS (10/32, 31.3%). The AFRS sequenced mycobiome was predominantly represented by Malassezia (43.6%), Curvularia (18.5%) and Aspergillus (16.8%), while the NF mycobiome was nearly exclusively Malassezia (84.2%) with an absence of Aspergillus or dematiaceous fungi.A low diversity, dysbiotic microenvironment dominated by Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae characterised the bacterial microbiome of AFRS, with a mycobiome abundant in Malassezia, Aspergillus and Curvularia. While Staphylococcus aureus has been previously implicated in AFRS through enterotoxin superantigen potential, Streptococcus pneumoniae and Haemophilus influenzae are novel findings that may represent alternate cross‐kingdom pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Haemophilus influenzae is a human respiratory pathogen and inhabits the human respiratory tract as its only niche. Despite this, the molecular mechanisms that allow H. influenzae to establish persistent infections of human epithelia are not well understood. Here, we have investigated how H. influenzae adapts to the host environment and triggers the host immune response using a human primary cell-based infection model that closely resembles human nasal epithelia (NHNE). Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, 'unproductive' inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state. This occurred in parallel with the development of intraepithelial bacterial populations, and appears to involve interruption of NFκB signalling. This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, and we were able to demonstrate that only infections with live, but not heat-killed H. influenzae led to immunomodulation and reduced expression of NFκB-controlled cytokines such as IL-1β, IL-36γ and TNFα. Interestingly, NHNE were able to re-activate pro-inflammatory responses towards the end of the 14-day infection, resulting in release of IL-8 and TNFα. In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation. Author summary: Respiratory tract infections are highly debilitating, and Haemophilus influenzae is a bacterial pathogen that is associated with persistent acute and chronic respiratory tract infections particularly in vulnerable parts of the population. Persistent infections rely on close molecular interactions between the human respiratory cells and the bacterial pathogen, and here we have investigated changes in host and bacterial cells during persistent, long-term infections with H. influenzae. We were able to show for the first time that H. influenzae infections can induce a tolerance to the presence of bacteria in human respiratory epithelia. This tolerance included reduced immune responses, and required live bacteria to be established, which indicates that H. influenzae likely produce specific effector molecules that interrupt immune system signalling. This is the first time that such interactions have been documented for H. influenzae, and suggests that future treatments for H. influenzae infections could include those that strengthen the human immune responses. [ABSTRACT FROM AUTHOR]

The multinuclear nonheme iron-dependent oxidases (MNIOs) are a rapidly growing family of enzymes involved in the biosynthesis of ribosomally synthesized, posttranslationally modified peptide natural products (RiPPs). Recently, a secreted virulence factor from nontypeable Haemophilus influenzae (NTHi) was found to be expressed from an operon, which we designate the hvf operon, that also encodes an MNIO. Here, we show by Mössbauer spectroscopy that the MNIO HvfB contains a triiron cofactor. We demonstrate that HvfB works together with HvfC [a RiPP recognition element (RRE)-containing partner protein] to perform six posttranslational modifications of cysteine residues on the virulence factor precursor peptide HvfA. Structural characterization by tandem mass spectrometry and NMR shows that these six cysteine residues are converted to oxazolone and thioamide pairs, similar to those found in the RiPP methanobactin. Like methanobactin, the mature virulence factor, which we name oxazolin, uses these modified residues to coordinate Cu(I) ions. Considering the necessity of oxazolin for host cell invasion by NTHi, these findings point to a key role for copper during NTHi infection. Furthermore, oxazolin and its biosynthetic pathway represent a potential therapeutic target for NTHi. [ABSTRACT FROM AUTHOR]

Introduction: The oropharyngeal microbiome plays an important role in protection against infectious agents when in balance. Despite use of vaccines and antibiotic therapy to prevent respiratory tract infections, they remain one of the major causes of mortality and morbidity in Low- and middleincome countries. Hence the need to explore other approaches to prevention by identifying microbial biomarkers that could be leveraged to modify the microbiota in order to enhance protection against pathogenic bacteria. The aim of this study was to analyze the oropharyngeal microbiome (OPM) of schoolchildren in Côte d’Ivoire presenting symptoms of upper respiratory tract infections (URTI) for better prevention strategy. Methods: Primary schools’ children in Korhogo (n = 37) and Abidjan (n = 39) were followed for six months with monthly oropharyngeal sampling. Clinical diagnostic of URT infection was performed and nucleic acid extracted from oropharyngeal swabs were used for 16S rRNA metagenomic analysis and RT-PCR. Results: The clinical examination of children’s throat in Abidjan and Korhogo identified respectively 17 (43.59%) and 15 (40.54%) participants with visible symptoms of URTIs, with 26 episodes of infection in Abidjan and 24 in Korhogo. Carriage of Haemophilus influenzae (12%), Streptococcus pneumoniae (6%) and SARS-CoV-2 (6%) was confirmed by PCR. A significant difference in alpha diversity was found between children colonized by S. pneumoniae and those that were not (p = 0.022). There was also a significant difference in alpha diversity between children colonised with H. influenzae and those who were not (p = 0.017). No significant difference was found for SARS-CoV-2. Sphingomonas, Ralstonia and Rothia were significantly enriched in non-carriers of S. pneumoniae; Actinobacillus was significantly enriched in non-carriers of H. influenzae; Actinobacillus and Porphyromonas were significantly enriched in non-carriers of SARS-CoV-2 (p < 0.001). Discussion: Nearly 40% of children showed clinical symptoms of infection not related to geographical location. The OPM showed an imbalance during H. influenzae and S. pneumoniae carriage. This study provides a baseline understanding of microbiome markers in URTIs in children for future research, to develop targeted interventions aimed at restoring the microbial balance and reducing the symptoms associated with RTIs. [ABSTRACT FROM AUTHOR]

A decreased chloramphenicol susceptibility in Haemophilus influenzae is commonly caused by the activity of chloramphenicol acetyltransferases (CATs). However, the involvement of membrane proteins in chloramphenicol susceptibility in H. influenzae remains unclear. In this study, chloramphenicol susceptibility testing, whole-genome sequencing, and analyses of membrane-related genes were performed in 51 H. influenzae isolates. Functional complementation assays and structure-based protein analyses were conducted to assess the effect of proteins with sequence substitutions on the minimum inhibitory concentration (MIC) of chloramphenicol in CAT-negative H. influenzae isolates. Six isolates were resistant to chloramphenicol and positive for type A-2 CATs. Of these isolates, A3256 had a similar level of CAT activity but a higher chloramphenicol MIC relative to the other resistant isolates; it also had 163 specific variations in 58 membrane genes. Regarding the CAT-negative isolates, logistic regression and receiver operator characteristic curve analyses revealed that 48T > G (Asn16Lys), 85 C > T (Leu29Phe), and 88 C > A (Leu30Ile) in HI_0898 (emrA), and 86T > G (Phe29Cys) and 141T > A (Ser47Arg) in HI_1177 (artM) were associated with enhanced chloramphenicol susceptibility, whereas 997G > A (Val333Ile) in HI_1612 (hmrM) was associated with reduced chloramphenicol susceptibility. Furthermore, the chloramphenicol MIC was lower in the CAT-negative isolates with EmrA-Leu29Phe/Leu30Ile or ArtM-Ser47Arg substitution and higher in those with HmrM-Val333Ile substitution, relative to their counterparts. The Val333Ile substitution was associated with enhanced HmrM protein stability and flexibility and increased chloramphenicol MICs in CAT-negative H. influenzae isolates. In conclusion, the substitution in H. influenzae multidrug efflux pump HmrM associated with reduced chloramphenicol susceptibility was characterised. [ABSTRACT FROM AUTHOR]

Background: Otitis media with effusion (OME) is a common childhood otological condition. The middle ear effusion is mucoid or seromucinous in nature, but not purulent. The condition lasts for at least 3 months; this sets it apart from persistent effusion after acute otitis media, which disappears after 2 months in 90% of cases. OME has a high prevalence in children and is responsible for most of the hearing losses in school going age group (5-12 years). Most cases of OME are relatively asymptomatic with nearly 25% discovered incidentally. Despite this apparent absence of symptoms, the potential impact on hearing, speech, language and cognition highlights the need for timely intervention. Aim: To estimate the risk factors associated with OME and to detect different types of microorganisms in the middle ear fluid of children with OME. Materials and Methods: A cross-sectional study was conducted on 458 children presenting with features of OME. A questionnaire was used to determine the risk factors for OME among these children. Otoscopy and tympanometry were used to diagnose and confirm OME. The pure tone average for children with OME was measured. Assessment of risk factors were done in all children. Myringotomy was performed in children with obvious fluid in the middle ear and a sample was sent for culture and sensitivity. Results: OME was highly linked with age less than 9 years in univariate analysis. The mean age of the sample was 8.71 years with the median age being 2.5 years. There are several risk factors related to OME, with nasal allergies (22.9%) and adenoid hypertrophy (22.9%) being the most prevalent. Middle ear fluid was sterile in 74.7% cases whereas 9% of the samples showed Streptococcus pneumoniae & Haemophilus influenzae as the microorganism. Conclusion: Nasal allergies and adenoid hypertrophy were the most common risk factors of OME in children less than 18 years. Otoscopy, tympanometry and pure tone audiometry should be used as screening tools for OME. Middle ear fluid was sterile in majority of cases and hence routine use of antibiotics for treatment of these cases is not recommended. [ABSTRACT FROM AUTHOR]