Haemophilus Influenzae Infection Research Articles

Changes in Invasive Neisseria meningitidis and Haemophilus influenzae Infections in France during the COVID-19 Pandemic.

BackgroundSince the appearance of COVID-19 in January 2020, invasive bacterial infections have decreased significantly worldwide. However, alterations in age and sex distributions, clinical forms, phenotypes, and genotypes of isolates have not been analyzed. Our goal is to present and discuss these data considering the current COVID-19 pandemic situation. Methods: The data of the national reference center for meningococci and Haemophilus influenzae in France were mined to examine the above aspects of invasive bacterial infection before (2018–2019) and after (2020–2021) the COVID-19 pandemic. Detailed epidemiological, clinical, and microbiological data were collected, and whole genome sequencing was carried out on meningococcal isolates (n = 1466). Results: In addition to the overall decline in the number of cases, various changes in age, sex, and phenotypes of isolates were also noted. As for N. meningitidis, more cases were observed in adults, as well as more invasive pneumopathies. Furthermore, fewer hyperinvasive meningococcal genotypes have circulated since COVID-19 emerged. The situation has been different for H. influenzae, as the number of invasive cases among adults decreased due to a reduction in non-typeable isolates. In contrast, cases due to serotypeable isolates, particularly serotypes a and b, increased in children <5 years-old. Conclusions: It is possible that measures implemented to stop COVID-19 may have reduced the circulation of N. meningitidis and H. influenzae isolates, but to a variable extent. This may be due to differences in circulation between these two species according to age groups. Vaccination schedules against these two species may have also influenced the evolution of these invasive bacterial infections since the emergence of the COVID-19 pandemic.

Access to highly specialized growth substrates and production of epithelial immunomodulatory metabolites determine survival of Haemophilus influenzae in human airway epithelial cells.

Haemophilus influenzae (Hi) infections are associated with recurring acute exacerbations of chronic respiratory diseases in children and adults including otitis media, pneumonia, chronic obstructive pulmonary disease and asthma. Here, we show that persistence and recurrence of Hi infections are closely linked to Hi metabolic properties, where preferred growth substrates are aligned to the metabolome of human airway epithelial surfaces and include lactate, pentoses, and nucleosides, but not glucose that is typically used for studies of Hi growth in vitro. Enzymatic and physiological investigations revealed that utilization of lactate, the preferred Hi carbon source, required the LldD L-lactate dehydrogenase (conservation: 98.8% of strains), but not the two redox-balancing D-lactate dehydrogenases Dld and LdhA. Utilization of preferred substrates was directly linked to Hi infection and persistence. When unable to utilize L-lactate or forced to rely on salvaged guanine, Hi showed reduced extra- and intra-cellular persistence in a murine model of lung infection and in primary normal human nasal epithelia, with up to 3000-fold attenuation observed in competitive infections. In contrast, D-lactate dehydrogenase mutants only showed a very slight reduction compared to the wild-type strain. Interestingly, acetate, the major Hi metabolic end-product, had anti-inflammatory effects on cultured human tissue cells in the presence of live but not heat-killed Hi, suggesting that metabolic endproducts also influence HI-host interactions. Our work provides significant new insights into the critical role of metabolism for Hi persistence in contact with host cells and reveals for the first time the immunomodulatory potential of Hi metabolites.

Haemophilus influenzae infection among children with acute bacterial meningitis.

Objective: To determine the frequency of haemophilus influenzae infection in children less than 5 years with acute bacterial meningitis (ABM). Study Design: Descriptive Cross Sectional study. Setting: Department of Pediatric Medicine, The Children’s Hospital and Institute of Child Health, Multan. Period: October 2019 to March 2020. Material &amp; Methods: A total of 165 children aged 5 – 60 months of either gender having acute bacterial meningitis with duration of &lt; 2 weeks were enrolled. Cerebrospinal fluid (CSF) of each child was sent for microbiological analysis. Results: There were 106 (64.2 %) boys and 59 (35.8 %) girls. Mean age was 2.72 ± 1.07 years. Most cases, 112 (67.9 %) belonged to urban areas. Maternal literacy was positive in 65 (39.4%) cases while 59 (35.8%) were fully vaccinated. Mean disease duration was 56.25 ± 15.36 hours and 112 (67.9%) had duration of illness more than 36 hours. Frequency of Haemophilus Influenzae was noted in 35 (21.2%) cases. Conclusion: Frequency of Haemophilus Influenzae was high among children with acute bacterial meningitis. Early diagnosis and appropriate management might help reducing prolonged hospitalization and disease morbidity related to Haemophilus Influenza.

Development and multimodal characterization of an elastase-induced emphysema mouse disease model for the COPD frequent bacterial exacerbator phenotype

ABSTRACT Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.

Particulate air pollution and respiratory Haemophilus influenzae infection in Mianyang, southwest China.

Particulate air pollution is correlated with many respiratory diseases. However, few studies have focused on the relationship between air particulate exposure and respiratory Heamophilus influenzae infection. Therefore, we detected respiratory Heamophilus influenzae infection by bacterial culture of sputum of patients, and we collected particulate air pollution data (including PM2.5 and PM10) from a national real-time urban air quality platform to analyze the relationship between particulate air pollution and respiratory Heamophilus influenzae infection. The mean concentrations of PM2.5 and PM10 were 37.58 μg/m3 and 58.44 μg/m3, respectively, showing particulate air pollution remains a severe issue in Mianyang. A total of 828 strains of Heamophilus influenzae were detected in sputum by bacterial culture. Multiple correspondence analysis suggested the heaviest particulate air pollution and the highest Heamophilus influenzae infection rates were all in winter, while the lowest particulate air pollution and the lowest Heamophilus influenzae infection rates were all in summer. In a single-pollutant model, each elevation of 10 μg/m3 of PM2.5, PM10, and PM2.5/10 (combined exposure level) increased the risk of respiratory Heamophilus influenzae infection by 34%, 23%, and 29%, respectively. Additionally, in the multiple-pollutant model, only PM2.5 was significantly associated with respiratory Heamophilus influenzae infection (B, 0.46; 95% confidence interval, 0.05-0.87), showing PM2.5 is an independent risk factor for respiratory Heamophilus influenzae infection. In summary, this study highlights air particulate exposure could increase the risk of respiratory Heamophilus influenzae infection, implying that stronger measures need to be taken to protect against respiratory infection induced by particulate air pollution.

Evaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspective

IntroductionIn Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. MethodsPharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. ResultsRegardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL− and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. ConclusionsOur study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.

Genomic insights of international clones of Haemophilus influenzae causing invasive infections in vaccinated and unvaccinated infants

The emergence of invasive Haemophilus influenzae infections in vaccinated patient is a public health concern. We have investigated the genomic basis of invasiveness and possible vaccine failure in H. influenzae causing invasive disease in vaccinated and unvaccinated children in Brazil. Three H. influenzae strains isolated from blood cultures of pediatric patients were sequenced. Serotype, MLST, resistome and virulome were predicted using bioinformatic tools, whereas single nucleotide polymorphisms (SNPs) analysis of cap loci and the presence of the putative virulence-enhancing IS1016-bexA partial deletion were predicted in silico. Infections were caused by H. influenzae type a (Hia), type b (Hib) and nontypeable (NTHi), belonging to international high-risk clones of sequence types ST23, ST6 and ST368, respectively, which have been identified in North American, European and Asian countries. Convergence of ampicillin resistance and virulence in Hib-ST6 was supported by blaTEM-1B and deletion in the bexA gene, whereas presence of SNPs in the cap-b locus was associated with antigenic modifications of the capsule structure. Hia-ST23 and NTHi-ST368 strains carried galU, lpsA, opsX, rfaF, iga1, lgtC and lic1/lic2 virulence genes, associated with colonization, adaptation and damage to the lung, or invasiveness. In summary, deletion in the bexA gene and presence of SNPs in the cap locus of Hib could be contributing to invasive disease and possible vaccine failure in pediatric patients, whereas serotype replacement of Hib with type “a” and NTHi strains denotes the ability of non-vaccine serotypes to re-colonize vaccinated patients. Finally, the dissemination of international high-risk clones of H. influenzae emphasizes the importance of monitoring changes in the molecular epidemiology of invasive H. influenzae disease.

Patent evaluation of US2019338018 (A1) 2019-11-07 (antibody fragments for the treatment of biofilm-related disorders)

ABSTRACT Introduction To date, microbial infections are also difficult to eradicate due to the increasing capability of bacteria to form a biofilm. In the era of antibiotic resistance, antibody-based approaches represent great promise in curing infective pathogens. The authors of US2019338018 patent propose a method for the treatment of biofilm-related disorders by using specific antibody fragments. Areas covered The US2019338018 patent reports antibody fragments, pharmaceutical composition that contains it, and their application for the treatment of biofilm-linked disorders. Proof concept and preclinical results show that mAb mIhfB4NTHI Fab caused robust eradication of the biofilm in the middle ear lumen of chinchillas affected by Hemophilus influenzae infection. Expert opinion Fab fragments of the US2019338018 patent are new in a general concept to treat bacterial biofilms and biofilm-linked disorders. However, pre-clinical data are only shown for the treatment with Fab fragments of infections caused by H. influenzae in the middle ear of chinchillas. There are no clinical trials that demonstrate that the treatment with Fab fragments may induce a disruption of biofilm produced by H. influenzae or other pathogens and an anti-inflammatory response in infected patients.

Invasive Haemophilus influenzae Infections in Germany After the Introduction of Routine Childhood Immunization, 2001-2016.

Background Haemophilus influenzae (Hi) serotype b (Hib) vaccination was introduced in Germany in 1990. This study presents a comprehensive overview on the burden of invasive Hi infections for 2001–2016, including serotype distribution and ampicillin resistance.MethodsNationwide data from statutory disease surveillance (2001–2016) were linked with laboratory surveillance data (2009–2016). Besides descriptive epidemiology, statistical analyses included multiple imputation to estimate secular trends.ResultsIn 2001–2016, 4044 invasive Hi infections were reported. The mean incidence was 3.0 per million inhabitants, higher in males (3.2 vs 2.9 in females) and in the age groups <1 year (15.2) and ≥80 years (15.5). Nontypeable Hi (NTHi) caused 81% (n = 1545) of cases in 2009–2016. Of capsulated cases, 69% were serotype f and 17% serotype b. Of Hib cases eligible for vaccination, 10% (3/29) were fully vaccinated. For 2009–2016, significant increasing trends were observed for NTHi and Hif infections in the age groups <5 years and ≥60 years and for ampicillin resistance in NTHi.ConclusionsThis is one of the most comprehensive Hi data analyses since the introduction of Hib vaccines. NTHi and Hif cause an increasing disease burden among elderly patients and infants. Ampicillin resistance in NTHi must be considered in the treatment of invasive Hi infections.

Invasive non-typeable Haemophilus influenzae infection due to endometritis associated with adenomyosis

BackgroundThe widespread administration of the Haemophilus influenzae type b vaccine has led to the predominance of non-typable H. influenzae (NTHi). However, the occurrence of invasive NTHi infection based on gynecologic diseases is still rare.Case presentationA 51-year-old Japanese woman with a history of adenomyoma presented with fever. Blood cultures and a vaginal discharge culture were positive with NTHi. With the high uptake in the uterus with 67Ga scintigraphy, she was diagnosed with invasive NTHi infection. In addition to antibiotic administrations, a total hysterectomy was performed. The pathological analysis found microabscess formations in adenomyosis.ConclusionsAlthough NTHi bacteremia consequent to a microabscess in adenomyosis is rare, this case emphasizes the need to consider the uterus as a potential source of infection in patients with underlying gynecological diseases, including an invasive NTHi infection with no known primary focus.

Evaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspective

IntroductionIn Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. MethodsPharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. ResultsRegardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL− and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. ConclusionsOur study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.

Molecular epidemiology of imipenem resistance in invasive Haemophilus influenzae infections in Germany in 2016

The carbapenems imipenem and meropenem play an important role in the empirical anti-infective treatment of critically ill patients. Carbapenem resistance in Haemophilus influenzae (Hi) has rarely been reported. We provide prevalence data for resistance to carbapenems from laboratory surveillance of invasive Hi infections in Germany in 2016. Phenotypic susceptibility testing against ampicillin, amoxicillin/clavulanate, cefotaxime and imipenem was carried out on 474 isolates from blood and CSF. The isolates were collected as part of the national laboratory surveillance programme. Imipenem-resistant strains were further tested for meropenem susceptibility. Molecular analysis was done by ftsI sequencing to detect mutations in PBP3, by acrR sequencing to detect alterations in the regulatory protein of the AcrAB-TolC efflux pump and by MLST. No resistance to meropenem was detected. Cefotaxime resistance was rare (n = 3; 0.6%). Imipenem resistance was found in 64 strains (13.5%) using gradient agar diffusion and was confirmed in 26 isolates by broth microdilution (5.5%). Imipenem resistance occurred predominantly in Hi that were β-lactamase negative but ampicillin resistant and in those that were β-lactamase positive but nevertheless amoxicillin/clavulanate resistant. This finding suggested a β-lactamase-independent mechanism. Accordingly, sequence analysis of PBP3 identified previously described mutations. MLST of the imipenem-resistant strains, which were all non-typeable Hi, revealed a high diversity. We conclude that imipenem, but not meropenem, resistance is frequent in Hi. It is likely to be supported by PBP3 mutations.

Comparative Analysis of Distribution and Drug Resistance of Haemophilus Influenzae Infection in Sputum Samples from Children and Elderly Patients

Comparative Analysis of Distribution and Drug Resistance of Haemophilus Influenzae Infection in Sputum Samples from Children and Elderly Patients

Extensively drug-resistant Haemophilus influenzae \u2013 emergence, epidemiology, risk factors, and regimen

BackgroundConcern about Haemophilus influenzae infection has been increasing over recent decades. Given the emergence of H. influenzae with severe drug resistance, we assessed the prevalence of as well as risk factors and potential therapies for extensively drug-resistant (XDR) H. influenzae infection in Taiwan.ResultsIn total, 2091 H. influenzae isolates with disk diffusion-based antibiotic susceptibility testing from 2007 to 2018 were enrolled. H. influenzae strains resistant to ampicillin, chloramphenicol, levofloxacin, and trimethoprim-sulfamethoxazole tended to be isolated from patient wards (≧41%), whereas those resistant to amoxicillin-clavulanate, cefotaxime, and cefuroxime were more likely to be isolated from intensive care units (approximately 50%). XDR H. influenzae was first identified in 2007, and its incidence did not significantly change thereafter. Overall prevalence of single, multiple, and extensively drug-resistant H. influenzae over 2007–2018 was 21.5% (n = 450), 26.6% (n = 557), and 2.5% (n = 52), respectively. A stepwise logistic regression analysis revealed that blood culture (odds ratio: 4.069, 95% confidence intervals: 1.339–12.365, P = 0.013) was an independent risk factor for XDR H. influenzae infection. No nosocomial transmission of XDR H. influenzae observed. Antibiotic susceptibility testing results demonstrated that cefotaxime was effective against 78.8% (n = 41) of the XDR strains.ConclusionsThe presence of XDR H. influenzae strains was identified in Taiwan, and cefotaxime was efficacious against most of these strains.

Detection of meningococcus, pneumococcus, Haemophilus influenzae, and group A streptococcus DNA in pediatric adenoid bioptats

Meningococcal, pneumococcal, streptococcal A and Haemophilus influenzae infections are manifested in different clinical forms, ranging from bacterial carriage to generalized life-threatening conditions. However, a connection between bacterial carriage and disease development has not been fully explored. A PCR assay was performed with adenoid biopsy samples collected from 112 children after planned adenotomy to detect Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus pyogenes, H. influenzae carriage. A DNA specific to at least one of the four studied microbial species was found in 104 samples (92.86%) so that: meningococcal DNA was detected in one sample (0.9%), pneumococcal — in 98 (87.5%), H. influenzae — in 19 (16.96%), and streptococcal A — in 42 (37.5%) samples. However, none of these species was found in 8 children (7.14%). A sole S. pneumoniae was detected in 54 samples (48.2%), whereas S. pyogenes — in 5 samples (4.5%). Moreover, two bacterial species were simultaneously as follows: N. meningitidis and S. pneumoniae — in 1 sample (0.9%), S. pneumoniae and H. influenzae — in 7 samples (6.3%); H. influenzae and S. pyogenes — in 1 sample (0.9%); S. pneumoniae and S. pyogenes — in 25 samples (22.3%). A triple combination consisting of S. pneumoniae, H. influenzae and S. pyogenes bacteria were detected together in 11 patients (9.8%). Meningococcal serogrouping revealed no connection with any of the 6 most common global serogroups responsible for epidemic incidence rise (A, B, C, W-135, X, Y). A clear tendency for prevalence of S. pyogenes DNA in adenoid pediatric biopsies in children diagnosed with “Adenoids and tonsils hypertrophy” vs. “Adenoids hypertrophy” was observed. It is noteworthy, a high relative prevalence of pneumococcal carriage (87.5%), found by us was of special importance. Pediatric carriers serving as a reservoir for virulent pneumococcal species pose a threat both for themselves and surrounding people. Thus, PCR-based data of adenoid biopsies may be a promising approach for future studies, as a potential to identify live viable but nonculturable bacteria in clinical specimens will contribute to a more accurate assessment of carriage rate of meningococci, pneumococci, H. influenzae and group A streptococci.

Haemophilus influenzae Glucose Catabolism Leading to Production of the Immunometabolite Acetate Has a Key Contribution to the Host Airway-Pathogen Interplay.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and impaired airway immunity, which provides an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. Clinical evidence supports that the COPD airways present increased concentrations of glucose, which may facilitate proliferation of pathogenic bacteria able to use glucose as a carbon source. NTHi metabolizes glucose through respiration-assisted fermentation, leading to the excretion of acetate, formate, and succinate. We hypothesized that such specialized glucose catabolism may be a pathoadaptive trait playing a pivotal role in the NTHi airway infection. To find out whether this is true, we engineered and characterized bacterial mutant strains impaired to produce acetate, formate, or succinate by inactivating the ackA, pflA, and frdA genes, respectively. While the inactivation of the pflA and frdA genes only had minimal physiological effects, the inactivation of the ackA gene affected acetate production and led to reduced bacterial growth, production of lactate under low oxygen tension, and bacterial attenuation in vivo. Moreover, bacterially produced acetate was able to stimulate the expression of inflammatory genes by cultured airway epithelial cells. These results back the notion that the COPD lung supports NTHi growth on glucose, enabling production of fermentative end products acting as immunometabolites at the site of infection. Thus, glucose catabolism may contribute not only to NTHi growth but also to bacterially driven airway inflammation. This information has important implications for developing nonantibiotic antimicrobials, given that airway glucose homeostasis modifying drugs could help prevent microbial infections associated with chronic lung disease.

Invasive Nontypeable Haemophilus influenzae Infection Among Adults With HIV in Metropolitan Atlanta, Georgia, 2008-2018

Invasive nontypeable Haemophilus influenzae (NTHi) infection among adults is typically associated with bacteremic pneumonia. Nontypeable H influenzae is genetically diverse and clusters of infection are uncommon. To evaluate an increase in invasive NTHi infection from 2017-2018 among HIV-infected men who have sex with men in metropolitan Atlanta, Georgia. A population-based surveillance study with a cohort substudy and descriptive epidemiological analysis identified adults aged 18 years or older with invasive NTHi infection (isolation of NTHi from a normally sterile site) between January 1, 2008, and December 31, 2018 (final date of follow-up). Time period, HIV status, and genetic relatedness (ie, cluster status) of available NTHi isolates. The primary outcome was incidence of invasive NTHi infection (from 2008-2016 and 2017-2018) among persons with HIV and compared with NTHi infection from 2008-2018 among those without HIV. The secondary outcomes were assessed among those aged 18 to 55 years with invasive NTHi infection and included epidemiological, clinical, and geographic comparisons by cluster status. Among 553 adults with invasive NTHi infection (median age, 66 years [Q1-Q3, 48-78 years]; 52% male; and 38% black), 60 cases occurred among persons with HIV. Incidence of invasive NTHi infection from 2017-2018 among persons with HIV (41.7 cases per 100 000) was significantly greater than from 2008-2016 among those with HIV (9.6 per 100 000; P < .001) and from 2008-2018 among those without HIV (1.1 per 100 000; P < .001). Among adults aged 18 to 55 years with invasive NTHi infections from 2017-2018 (n = 179), persons with HIV (n = 31) were significantly more likely than those from 2008-2018 without HIV (n = 124) to be male (94% vs 49%, respectively; P < .001), black (100% vs 53%; P < .001), and have septic arthritis (35% vs 1%; P < .001). Persons with HIV who had invasive NTHi infection from 2017-2018 (n = 31) were more likely than persons with HIV who had invasive NTHi infection from 2008-2016 (n = 24) to have septic arthritis (35% vs 4%, respectively; P = .01). Pulsed-field gel electrophoresis of 174 of 179 NTHi isolates from 18- to 55-year-olds identified 2 genetically distinct clonal groups: cluster 1 (C1; n = 24) and cluster 2 (C2; n = 23). Whole-genome sequencing confirmed 2 clonal lineages of NTHi infection and revealed all C1 isolates (but none of the C2 isolates) carried IS1016 (an insertion sequence associated with H influenzae capsule genes). Persons with HIV were significantly more likely to have C1 or C2 invasive NTHi infection from 2017-2018 (28/31 [90%]) compared with from 2008-2016 among persons with HIV (10/24 [42%]; P < .001) and compared with from 2008-2018 among those without HIV (9/119 [8%]; P < .001). Among persons with C1 or C2 invasive NTHi infection who had HIV (n = 38) (median age, 34.5 years; 100% male; 100% black; 82% men who have sex with men), 32 (84%) lived in 2 urban counties and an area of significant spatial aggregation was identified compared with those without C1 or C2 invasive NTHi infection. Among persons with HIV in Atlanta, the incidence of invasive nontypeable H influenzae infection increased significantly from 2017-2018 compared with 2008-2016. Two unique but genetically related clonal strains were identified and were associated with septic arthritis among black men who have sex with men and who lived in geographic proximity.

Preclinical Evaluation of the Antimicrobial-Immunomodulatory Dual Action of Xenohormetic Molecules against Haemophilus influenzae Respiratory Infection.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammation and impaired airway immunity, providing an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. In this context, therapies targeting not only overactive inflammation without significant adverse effects, but also infection are of interest. Increasing evidence suggests that polyphenols, plant secondary metabolites with anti-inflammatory and antimicrobial properties, may be protective. Here, a Cistus salviifolius plant extract containing quercetin, myricetin, and punicalagin was shown to reduce NTHi viability. Analysis of these polyphenols revealed that quercetin has a bactericidal effect on NTHi, does not display synergies, and that bacteria do not seem to develop resistance. Moreover, quercetin lowered NTHi airway epithelial invasion through a mechanism likely involving inhibition of Akt phosphorylation, and reduced the expression of bacterially-induced proinflammatory markers il-8, cxcl-1, il-6, pde4b, and tnfα. We further tested quercetin’s effect on NTHi murine pulmonary infection, showing a moderate reduction in bacterial counts and significantly reduced expression of proinflammatory genes, compared to untreated mice. Quercetin administration during NTHi infection on a zebrafish septicemia infection model system showed a bacterial clearing effect without signs of host toxicity. In conclusion, this study highlights the therapeutic potential of the xenohormetic molecule quercetin against NTHi infection.

Non-typeable Haemophilus influenzae-associated early pregnancy loss: an emerging neonatal and maternal pathogen

ObjectivesThere is increasing evidence indicating an association between invasive non-typeable Haemophilus influenzae (NTHi) infection in pregnancy and early pregnancy loss. As the diagnosis relies on microbiological investigation of post-mortem placental and foetal samples, a significant proportion of NTHi-related pregnancy loss remains unrecognised. To better characterise NTHi in septic abortion, we report NTHi cases associated with early pregnancy loss.MethodsWe reviewed all post-mortems at <24 weeks gestation with histologically proven acute chorioamnionitis on placental histology and enrolled cases with at least one matched foetal and placental sample culture positive for NTHi. The study was approved by the NHS Lothian Caldicott Guardian.ResultsIn our cohort, invasive NTHi has accounted for 20% of infections associated with early pregnancy loss prior to 24 weeks gestation. All patients were young and healthy pregnant women at < 20 weeks' gestation who presented with abdominal pain, PV bleed /discharge and were septic at the time of presentation. One patient with previous history of miscarriage who presented with cervical incompetence had more severe pathology suggestive of early intrauterine pneumonia.ConclusionThe burden of invasive NTHi disease in early pregnancy loss is likely to be much larger than currently recognised. NTHi should be considered in pregnant women presenting with abdominal pain and PV bleed/discharge in whom clinical signs of sepsis are present. Active surveillance should be considered in this patient group including septic abortion to capture the true prevalence of this emerging pathogen to inform preventative and therapeutic approaches.

Expert consensus on diagnosis and treatment of Haemophilus influenzae infection in children

流感嗜血杆菌（HI）感染是儿童常见的疾病，临床以菌血症、脑膜炎、肺炎、中耳炎、鼻窦炎和外阴阴道炎常见。目前引起感染的HI菌型以不定型菌株为主，侵袭性感染临床症状较严重。病原诊断包括各种标本的培养、核酸检测、抗原抗体检测。近年HI耐药日益严重，但对第三代头孢菌素敏感性较高。本建议在阐述HI病原学、疾病负担、细菌耐药性和临床表现的基础上，对本病的诊断、抗感染治疗策略提出建议，对疫苗预防提出新的思考。.