Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial.

Importance: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. Design, Setting, and Participants: This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. Interventions: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. Main Outcomes and Measures: The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. Results: Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). Conclusions and Relevance: In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. Trial Registration: ClinicalTrials.gov identifier: NCT03183141.

Assessment of Quality of Life Among Patients With Recurrent Clostridioides difficile Infection Treated with Investigational Oral Microbiome Therapeutic SER-109: Secondary Analysis of a Randomized Clinical Trial.

Importance: Recurrent Clostridioides difficile infection (CDI) is a debilitating disease leading to poor health-related quality of life (HRQOL), loss of productivity, anxiety, and depression. The potential association of treatment with HRQOL has not been well evaluated. Objectives: To explore the association of SER-109 compared with placebo on HRQOL in patients with recurrent CDI up to week 8. Design, Setting, and Participants: This study was a secondary analysis of a randomized, double-blind, placebo-controlled trial that took place at 56 sites in the US and Canada from July 2017 to April 2020 and included 182 patients randomized to SER-109 or placebo groups. Interventions: SER-109 or placebo (4 capsules once daily for 3 days) following antibiotics for CDI. Main Outcomes and Measures: Exploratory analysis of HRQOL using the disease specific Clostridioides difficile Quality of Life Survey (Cdiff32) assessed at baseline, week 1, and week 8. Results: In this study, 182 patients (109 [59.9%] female; mean age, 65.5 [16.5] years) were randomized to SER-109 (89 [48.9%]) or placebo (93 [51.1%]) groups and were included in the primary and exploratory analyses. Baseline Cdiff32 scores were similar between patients in the SER-109 and placebo groups (52.0 [18.3] vs 52.8 [18.7], respectively). The proportion of patients with overall improvement from baseline in the Cdiff32 total score was higher in the SER-109 arm than placebo at week 1 (49.4% vs 26.9%; P = .012) and week 8 (66.3% vs 48.4%; P = .001).Greater improvements in total and physical domain and subdomain scores were observed in patients in the SER-109 group compared with placebo as early as week 1, with continued improvements observed at week 8. Among patients in the placebo group, improvements in HRQOL were primarily observed in patients with nonrecurrent CDI while patients in the SER-109 group reported improvements in HRQOL, regardless of clinical outcome. Conclusions and Relevance: In this secondary analysis of a phase 3 clinical trial, SER-109, an investigational microbiome therapeutic was associated with rapid and steady improvement in HRQOL compared with placebo through 8 weeks, an important patient-reported outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03183128.

Novel case of empyema necessitans caused by Mycobacterium xenopi.

Poorly controlled long-standing empyema can dissect through soft tissues and skin resulting in empyema necessitans. We present the first reported case of empyema necessitans caused by Mycobacterium xenopi, which was treated successfully with antimycobacterial therapy. The case highlights the indolent nature of the pathogen and the importance of an accurate diagnosis.

BK virus associated with small cell carcinoma of bladder in a patient with renal transplant.

A man in his 70s with a complex medical history, including cadaveric renal transplant, presented with recurrent urinary tract infections. Investigation revealed recurrent urinary pathogens, including Enterobacter cloacae and persistent BK viruria. Cystoscopy revealed a pedunculated mass in the right posterior-lateral wall, inferior to the transplant urethral orifice, and biopsy of this mass showed invasive small cell carcinoma with a prominent adenocarcinoma component. The tumour was treated with complete transurethral resection followed by carboplatin, etoposide and radiation. Laboratory analysis of biopsied samples showed immunostaining and molecular evidence of BK virus DNA in the cancer cells. Follow-up cystoscopies have shown no recurrence of the cancer.

SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).

Compartmentalization of anti-oxidant and anti-inflammatory gene expression in current and former smokers with COPD.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have high oxidative stress associated with the severity of the disease. Nuclear factor erythroid-2 related factor 2 (Nrf2)-directed stress response plays a critical role in the protection of lung cells to oxidative stress by upregulating antioxidant genes in response to tobacco smoke. There is a critical gap in our knowledge about Nrf-2 regulated genes in active smokers and former-smokers with COPD in different cell types from of lungs and surrogate peripheral tissues. METHODS: We compared the expression of Nrf2 and six of its target genes in alveolar macrophages, nasal, and bronchial epithelium and peripheral blood mononuclear cells (PBMCs) in current and former smokers with COPD. We compared cell-type specific of Nrf2 and its target genes as well as markers of oxidative and inflammatory stress. RESULTS: We enrolled 89 patients; expression all Nrf2 target gene measured were significantly higher in the bronchial epithelium from smokers compared to non-smokers. None were elevated in alveolar macrophages and only one was elevated in each of the other compartments. CONCLUSION: Bronchial epithelium is the most responsive tissue for transcriptional activation of Nrf2 target genes in active smokers compared to former-smokers with COPD that correlated with oxidative stress and inflammatory markers. There were no consistent trends in gene expression in other cell types tested. TRIAL REGISTRATION: Clinicaltrials.gov : NCT01335971.

Successful cure of daptomycin-non-susceptible, vancomycin-intermediate Staphylococcus aureus prosthetic aortic valve endocarditis directed by synergistic in vitro time-kill study.

Infectious complications following surgical valve replacements are extremely difficult to treat, often requiring prolonged antimicrobials therapy with or without surgery. Vancomycin-intermediate Staphylococcus aureus is an infrequent pathogen, with an estimated prevalence of less than 0.3%, but presents even greater challenges. We report a case of successful cure of daptomycin-non-susceptible and vancomycin-intermediate Staphylococcus aureus prosthetic valve endocarditis using an eight-week course of combination antimicrobial therapy. Using time-kill study, the combination of daptomycin plus ceftaroline and rifampin resulted in a greater than 4 log reduction of bacterial growth at 24 hours. This antimicrobial combination was used for a total of eight weeks with a successful outcome.

Sialic Acid-Dependent Inhibition of T Cells by Exosomal Ganglioside GD3 in Ovarian Tumor Microenvironments.

The tumor microenvironment is rendered immunosuppressive by a variety of cellular and acellular factors that represent potential cancer therapeutic targets. Although exosomes isolated from ovarian tumor ascites fluids have been previously reported to induce a rapid and reversible T cell arrest, the factors present on or within exosomes that contribute to immunosuppression have not been fully defined. In this study, we establish that GD3, a ganglioside expressed on the surface of exosomes isolated from human ovarian tumor ascites fluids, is causally linked to the functional arrest of T cells activated through their TCR. This arrest is inhibited by Ab blockade of exosomal GD3 or by the removal of GD3+ exosomes. Empty liposomes expressing GD3 on the surface also inhibit the activation of T cells, establishing that GD3 contributes to the functional arrest of T cells independent of factors present in exosomes. Finally, we demonstrate that the GD3-mediated arrest of the TCR activation is dependent upon sialic acid groups, because their enzymatic removal from exosomes or liposomes results in a loss of inhibitory capacity. Collectively, these data define GD3 as a potential immunotherapeutic target.

Successful treatment of multidrug-resistant Pseudomonas aeruginosa pubic symphysis osteomyelitis with ceftolozane/tazobactam.

New antibiotic options are needed for the treatment of multidrug-resistant (MDR) Pseudomonas infections. We present a case of a man aged 64 years with a bladder fistula due to radiation, ultimately causing osteomyelitis of the pubic symphysis. Repeated antibiotic courses, without correcting the fistula, resulted in infection with MDR Pseudomonas aeruginosa. He was successfully treated for his osteomyelitis through cystectomy, aggressive debridement and a prolonged course of antimicrobials directed at the MDR Pseudomonas isolate.

Correction: Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial.

[This corrects the article DOI: 10.1371/journal.pone.0163716.].

Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial.

BACKGROUND: COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). METHODS: This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 µmoles, or 150 µmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. RESULTS: Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels. CONCLUSION: Sulforaphane administered for four weeks at doses of 25 µmoles and 150 µmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01335971.

Native valve Proteus mirabilis endocarditis: successful treatment of a rare entity formulated by in vitro synergy antibiotic testing.

Infective endocarditis caused by Proteus mirabilis is a rare and poorly reported disease, with no well-defined effective antibiotic regimen. Here, we present a case of P. mirabilis aortic valve endocarditis. We reviewed prior cases and treatment regimens, and devised effective treatment, which was guided by in vitro sensitivity and synergy testing on the pathogen. Our patient survived without complications or the need for a surgical intervention.

Burkholderia ginsengisoli bacteraemia: emergence of a novel pathogen.

Burkholderia ginsengisoli is a non-pathogenic Gram-negative bacterium that ordinarily serves as a plant endosymbiont. We report the first case of human infection with B. ginsengisoli presenting as bacteraemia in a young man with severe Crohn's disease. Definitive identification of the pathogen could not be accomplished with conventional techniques and required DNA sequencing. The bacteraemia may have been related to ingestion of organic vegetables and compromised gastrointestinal mucosa, coupled with treatment with tumour necrosis factor α inhibitors. Although there are no standard antibiotics to treat this pathogen, we devised a successful treatment regimen.

The Impact of Exogenous Factors on Respiratory Pathogen-Induced Innate Alveolar Macrophage Responses in COPD.

Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have fundamentally impaired innate immune responses to toll-like receptor (TLR) ligands of nontypeable Haemophilus influenzae (NTHI). However, whether dysfunctional inflammatory responses in COPD extend to macrophage interactions with intact respiratory pathogens beyond NTHI has not been explored. Furthermore, the influences of exogenous factors, including active smoking and medications, on pathogen-induced innate immune responses have only begun to be investigated. We hypothesized that distinct alveolar macrophage impairments in COPD are not limited to NTHI TLR ligands and that active smoking and select COPD medications modulate innate responses. Alveolar macrophages, obtained from COPD ex-smokers (n = 32) and active smokers (n = 64) by bronchoalveolar lavage (BAL), were incubated with NTHI, Moraxella catarrhalis, and Streptococcus pneumoniae, and with TLR2 and TLR4 ligands. Elicited IL-8 and TNF-α were measured by multianalyte microsphere flow cytometry to determine proinflammatory responsiveness. Induced IL-8, but not TNF-α, was greater from alveolar macrophages of active smokers compared with ex-smokers, in response to NTHI (p = 0.04), M. catarrhalis (p = 0.003), and S. pneumoniae (p = 0.03). Both IL-8 and TNF-α induction by TLR2 and TLR4 ligands were greater in active smokers. While intergroup NTHI- and M. catarrhalis-induced TNF-α levels were no different, they were notably lower among ex-smokers taking anticholinergic medications (p < 0.04 for each), but not with any other bronchoactive medications. Our results support a paradigm of distinct immunologic responses of COPD alveolar macrophages of ex- and active smokers to diverse respiratory pathogens and highlight a subset of ex-smokers whose diminished alveolar macrophage responsiveness may be associated with anticholinergic agents.

Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms.

BACKGROUND: Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C). METHODS: DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined. RESULTS: No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037). CONCLUSION: Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.

Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade.

The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients' antitumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T-cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80 nm. The T-cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS-expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle-induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immunosuppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T-cell function represent a potential therapeutic target for patients with ovarian cancer.

Impaired innate immune alveolar macrophage response and the predilection for COPD exacerbations.

BACKGROUND: Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity. METHODS: AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam3Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non-parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals. RESULTS: 29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each). CONCLUSIONS: Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.

Non-typeable Haemophilus influenzae infective endocarditis in a renal transplant recipient: compromised host or virulent strain?

Non-typeable Haemophilus influenzae (NTHI) rarely cause endocarditis. Of the limited reports of H influenzae endocarditis, most have been due to encapsulated organisms or have had limited bacterial characterisation. We encountered a transplant recipient with native valve NTHI endocarditis and were intrigued to find no previous descriptions of this entity. Although it was tempting to ascribe this infection to our patient's immunocompromised status, we investigated his pathogen further and found that it displayed features common to invasive NTHI strains including gene expression for two IgA proteases and serum resistance. Multilocus sequence typing grouped our NTHI strain with MLST 159, a group associated with invasive NTHI infections. Our strain shared identical outer membrane protein P2 sequences and protein patterns with MLST 159 strains. Aside from providing the first characterisation of native valve NTHI infection, our investigation reveals features of epidemiologically unrelated, clonal NTHI strains that have a predilection for invasive infections.

Phagocytic dysfunction of human alveolar macrophages and severity of chronic obstructive pulmonary disease.

BACKGROUND: Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have fundamental impairment of phagocytosis for nontypeable Haemophilus influenzae (NTHI). However, relative selectivity of dysfunctional phagocytosis among diverse respiratory pathogens: NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP), and nonbacterial particles, as well as the contribution of impaired phagocytosis to severity of COPD, has not been explored. METHODS: Alveolar macrophages, obtained from nonsmokers (n = 20), COPD ex-smokers (n = 32), and COPD active smokers (n = 64), were incubated with labeled NTHI, MC, SP, and fluorescent microspheres. Phagocytosis was measured as intracellular percentages of each. RESULTS: Alveolar macrophages of COPD ex-smokers and active smokers had impaired complement-independent phagocytosis of NTHI (P = .003) and MC (P = .0007) but not SP or microspheres. Nonetheless, complement-mediated phagocytosis was enhanced within each group only for SP. Defective phagocytosis was significantly greater for NTHI than for MC among COPD active smokers (P < .0001) and ex-smokers (P = .028). Moreover, severity of COPD (FEV1%predicted) correlated with impaired AM phagocytosis for NTHI (P = .0016) and MC (P = .01). CONCLUSIONS: These studies delineate pathogen- and host-specific differences in defective alveolar macrophages phagocytosis of respiratory bacteria in COPD, further elucidating the immunologic basis for bacterial persistence in COPD and provide the first demonstration of association of impaired phagocytosis to severity of disease.