Rima A Moghnieh, Zeina A Kanafani, Hussam Z Tabaja, Sima L Sharara, Lyn S Awad, Souha S Kanj

No uniformly organised collection of data regarding antimicrobial resistance has occurred in the countries of the Arab League. 19 countries of the Arab League have published data for antimicrobial susceptibility for the WHO priority organisms, and seven of 14 of these organisms are included in this Review (Escherichia coli, Klebsiella spp, Pseudomonas aeruginosa, Acinetobacter baumannii, Salmonella spp, Staphylococcus aureus, and Streptococcus pneumoniae). Although E coli and Klebsiella spp resistance to third-generation cephalosporins is common in all countries, with prevalence reaching more than 50% in Egypt and Syria, carbapenem resistance is emerging, albeit with a prevalence of less than 10%.

Juttukonda, L. J., Green, E. R., Lonergan, Z. R., Heffern, M. C., Chang, C. J., Skaar, E. P.

Acinetobacter baumannii is a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms, A. baumannii isolates are commonly multi-drug resistant and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistant A. baumannii as a ‘critical priority’ for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover mechanisms used by A. baumannii to survive stresses encountered during infection in order to identify new drug targets. In this study, we identified hydrogen peroxide (H2O2) as a stressor produced in the lung during A. baumannii infection using in vivo imaging and defined OxyR as a transcriptional regulator of the H2O2 stress response. Upon exposure to H2O2, A. baumannii differentially transcribes several hundred genes. However, transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in A. baumannii genetically inactivated for the transcriptional regulator oxyR. Moreover, inactivation of oxyR in both antimicrobial-susceptible and multi-drug-resistant A. baumannii strains impairs growth in the presence of H2O2. OxyR is a direct regulator of katE and ahpF1, which encode the major H2O2-degrading enzymes in A. baumannii, as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, an oxyR mutant is less fit than wild-type A. baumannii during infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive H2O2 stress encountered during infection.

Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic

by Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic After three national point prevalence studies (PPS) of healthcare associated infections (HAI) conducted in Serbian acute care hospitals using US (CDC/NHSN) surveillance definitions, Serbia is about to switch to European (ECDC) criteria for the purpose of the fourth HAI PPS. The aim of this study was to compare the US and the European HAI definitions in Serbian trauma intensive care unit (ICU). Prospective surveillance was performed at two surgical-trauma ICUs of the Emergency department of Clinical Center of Serbia. HAIs were prospectively diagnosed by experienced clinician and epidemiologists using both types of HAI definitions simultaneously. The level of agreement between two case definitions was assessed by Cohen’s kappa statistic (k). Of 406 patients, 107 (26.3%) acquired at least one HAI (total of 107 according to US definitions and 141 according to European criteria). For microbiologically confirmed pneumonia agreement was k = 0.99 (95% CI, 0.96–1.00) and for clinically defined k = 0.86 (95% CI, 0.58–1.00). Agreement for bloodstream infections (BSI) was 0.79 (CI 95%, 0.70–0.89). When secondary BSI was excluded from the European classification, (30.9% of all BSI), concordance was k = 1.00 and when microbiologically confirmed catheter related BSI were reported separately as recommended by latest ECDC protocol update, (20.0% of all BSI), concordance was 0.60 (CI 95%, 0.41–0.80). No agreement was found between CLABSI and CRI while slight agreement was found when compared CLABSI and CRI3 (k = 0.11; 95%CI, 0.0–0.22). Agreement for overall UTI was moderate (k = 0.66; 95%CI, 0.53–0.79) while for microbiologically-confirmed symptomatic UTI was perfect (k = 1.00). For CAUTI good agreement was observed (k = 0.77; 95%CI, 0.34–1.0). Microbiological confirmation of PN and UTI should be stimulated and comparison of BSI should be done with emphasis on whether secondary BSI is included.

Helio S. Sader, Robert K. Flamm, Jennifer M. Streit, Cecilia G. Carvalhaes, Rodrigo E. Mendes

E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld

by E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld For managing overactive bladder (OAB), mirabegron, a β3 adrenergic receptor agonist, is typically used as second-line pharmacotherapy after antimuscarinics. Therefore, patients initiating treatment with mirabegron and antimuscarinics may differ, potentially impacting associated clinical outcomes. When using observational data to evaluate real-world safety and effectiveness of OAB treatments, residual bias due to unmeasured confounding and/or confounding by indication are important considerations. Falsification analysis, in which clinically irrelevant endpoints are tested as a reference, can be used to assess residual bias. The objective in this study was to compare baseline cardiovascular risk among OAB patients by treatment, and assess the presence of residual bias via falsification analysis of OAB patients treated with mirabegron or antimuscarinics, to determine whether clinically relevant comparisons across groups would be feasible. Linked electronic health record and claims data (Optum/Humedica) for OAB patients in the United States from 2011–2015 were available, with index defined as first date of OAB treatment during this period. Unadjusted characteristics were compared across groups at index and propensity-matching conducted. Falsification endpoints (hepatitis C, shingles, community-acquired pneumonia) were compared between groups using odds ratios (ORs) and 95% confidence intervals (CI). The study identified 10,311 antimuscarinic- and 408 mirabegron-treated patients. Mirabegron patients were predominantly older males, with more comorbidities. The analytic sample included 1,188 antimuscarinic patients propensity-matched to 396 mirabegron patients; after matching, no significant baseline differences remained. Estimates of falsification ORs were 0.7 (CI:0.3–1.7) for shingles, 1.5 (CI:0.3–8.2) for hepatitis C, 0.8 (CI:0.4–1.8) and 0.9 (CI:0.6–1.4) for pneumonia. While propensity matching successfully balanced observed covariates, wide CIs prevented definitive conclusions regarding residual bias. Accordingly, further observational comparisons by treatment group were not pursued. In real-world analysis, bias-detection methods could not confirm that differences in cardiovascular risk in patients receiving mirabegron versus antimuscarinics were fully adjusted for, precluding clinically relevant comparisons across treatment groups.

Wuerth, K., Lee, A. H. Y., Falsafi, R., Gill, E. E., Hancock, R. E. W.

Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multi-drug resistance are becoming more prevalent. Here we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo. IDR-1002 significantly reduced the bacterial burden in the bronchoalveolar lavage fluid (BALF) as well as MCP-1 in the BALF and serum, KC in the serum, and IL-6 in the BALF. RNA-Seq was conducted on lungs and whole blood and the effects of P. aeruginosa, IDR-1002, or the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results show that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.

Kazuki Hatayama, Nobuyuki Nosaka, Mutsuko Yamada, Masato Yashiro, Yosuke Fujii, Hirokazu Tsukahara, Keyue Liu, Masahiro Nishibori, Akihiro Matsukawa, Tsuneo Morishima

Abstract Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury (ALI) due to excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti‐inflammatory effect of anti‐high‐mobility group box‐1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti‐HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine‐week‐old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post‐infection (dpi). The anti‐HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti‐HMGB1 mAb significantly improved survival rate whereas the anti‐HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti‐HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti‐HMGB1 with conventional anti‐influenza therapy might be useful against severe influenza virus infection. This article is protected by copyright. All rights reserved.

Girlich, D., Naas, T., Dortet, L.

The dissemination of carbapenemase-producing Enterobacteriaceae (CPE), has led to the increased use of colistin, which resulted in the emergence of colistin-resistant Enterobacteriaceae worldwide. One of the most threatening scenarios is the dissemination of colistin-resistance in CPE, particularly the plasmid-encoded resistance MCR. Thus, it becomes now mandatory to possess reliable media to screen for colistin-resistant Gram-negative isolates, especially Enterobacteriaceae. In this study we evaluated the performances of the Superpolymyxin™medium (ELITechGroup) and the CHROMID® Colistin R (bioMérieux) to screen for colistin-resistant Enterobacteriaceae from spiked rectal swabs. Stools were spiked with a total of 94 enterobacterial isolates (Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Enterobacter cloacae), including 53 colistin-resistant isolates. ESwabs™(Copan Diagnostics) were then inoculated with those spiked fecal suspensions and proceed as recommended by both manufacturers. The sensitivity of detection colistin-resistant Enterobacteriaceae were of 86.8% [95% confidence interval (CI95) 74.0 – 94.0] using both the Superpolymyxin™medium and the CHROMID® Colistin R plates. Surprisingly, the isolates that were not detected were not the same for both media. The specificities were high for both media, at 97.9% [CI95 = 87.3% - 99.9%] for Superpolymyxin™medium and 100% [CI95 = 90.4% - 100%] for the CHROMID® Colistin R medium. Both commercially-available media, CHROMID® Colistin R and Superpolymyxin™, provide a useful tool to screen for colistin-resistant Enterobacteriaceae from patient samples (rectal swabs) regardless of the level and mechanism of colistin resistance.

Sakamoto, N., Akeda, Y., Sugawara, Y., Takeuchi, D., Motooka, D., Yamamoto, N., Laolerd, W., Santanirand, P., Hamada, S.

We report here the K. pneumoniae strains carrying chromosomal blaNDM-1 in Thailand. The genomes of these two isolates include a 160-kbp insertion containing blaNDM-1, which is almost identical to that in the IncHI1B-like plasmid. Further analysis indicated that IS5-mediated intermolecular transposition and Tn3-transposase-mediated homologous recombination resulted in the integration of blaNDM-1 into the chromosome from an IncHI1B-like plasmid. The spread of this type of carbapenem-resistant Enterobacteriaceae may threaten public health and warrants further monitoring.

Ruggeri, Tiphaine; Jacqueline, Cédric; Ambrosi, Xavier; Broquet, Alexis; Desfrançois, Juliette; Roquilly, Antoine; Altare, Frédéric; Asehnoune, Karim

Objectives: In patients with spinal cord injury, spinal cord injury-immune depression syndrome induces pneumonia. We aimed to develop a new spinal cord injury-immune depression syndrome mouse model and to test antiprogrammed cell death 1 therapy. Design: Experimental study. Setting: Research laboratory. Subjects: RjOrl: SWISS and BALB/cJ mice. Interventions: Mouse model of spinal cord injury-immune depression syndrome followed by a methicillin-susceptible Staphylococcus aureus pneumonia. Lung injuries were assessed by histologic analysis. Membrane markers and intracytoplasmic cytokines were assessed by flow cytometry. Cytokine production was assessed by quantitative polymerase chain reaction (messenger RNA) and enzyme-linked immunosorbent assay (protein). Animals were treated with blocking antiprogrammed cell death 1 antibodies (intraperitoneal injection). Measurements and Main Results: Spinal cord injury mice were more susceptible to methicillin-susceptible S. aureus pneumonia (increased mortality rate). An early inflammatory response was observed in spinal cord injury mice characterized in lungs by a decreased percentage of aerated tissue, an increased production of proinflammatory cytokines (tumor necrosis factor-α). In spleen, an increased expression of major histocompatibility complex class II molecules on dendritic cells, and an increased production of proinflammatory cytokines (interleukin-12, interferon-γ) was observed. Following this pulmonary and systemic inflammation, spinal cord injury-immune depression syndrome was observed in spleens as acknowledged by a decrease of spleen’s weight, a lymphopenia, a decrease of major histocompatibility complex class II expression on dendritic cells. An increase of interleukin-10 production and the increase of a cell exhaustion marker expression, programmed cell death 1 receptor on T-cell were also observed. Blockade of programmed cell death 1 molecules, improved survival of spinal cord injury infected mice and enhanced interferon-γ production by natural killer T cells as well as number of viable CD4+ T cells. Conclusions: This model of spinal cord injury in mice mimics a clinical scenario rendering animals prone to a secondary pneumonia. We show for the first time an acute T-cell exhaustion-like phenomenon following an initial inflammatory response. Finally, inhibition of exhaustion pathway should be considered as a new therapeutic option to overcome spinal cord injury-immune depression syndrome and to decrease the rate of nosocomial pneumonia. Ms. Ruggeri and Dr. Jacqueline contribute equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Asehnoune received funding from Baxter, Fresenius, and Fisher & Paykel. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: karim.asehnoune@chu-nantes.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Amaral E, Machado de Salles É, Barbosa Bomfim C, et al.

AbstractBackgroundTuberculous pneumonia, necrotic granulomatous lesions, and bacterial dissemination characterize severe forms of mycobacterial infection.MethodsTo evaluate the pulmonary CD4+ T-cell response during severe tuberculosis, C57BL/6 mice were infected with approximately 100 bacilli of 3 hypervirulent mycobacterial isolates (Mycobacterium tuberculosis strain Beijing 1471 and Mycobacterium bovis strains B2 and MP287/03) or the H37Rv M tuberculosis strain as reference for mycobacterial virulence. Because high expression of both CD39 and CD73 ectonucleotidases was detected on parenchymal CD4+ T cells, we investigated whether CD4+ T-cell suppression in the context of severe disease was due to the extracellular adenosine accumulation that resulted from tissue damage.ResultsLowest expression of CD69, which is an activation marker implicated in maintaining cells in tissues, was observed in lungs from mice displaying the most severe pulmonary pathology. Reduced interferon (IFN)γ-producing CD4+ T cells were also found in the lung of these mice. Intranasal administration of the adenosine receptor antagonist caffeine substantially enhanced the frequency and number of parenchymal CD4+ T cells as well as both CD69 expression and IFNγ production.ConclusionsThese results indicate that adenosine, which may be generated by extracellular adenosine triphosphate degradation, impairs the parenchymal CD4+ T-cell response and contributes to the development of severe tuberculosis.

Yong, Michelle K.; Slavin, Monica; Kontoyiannis, Dimitrios P.

Purpose of review Invasive fungal disease (IFD) and cytomegalovirus (CMV) infections occur frequently, either concomitantly or sequentially in immune compromised hosts. While there is extensive knowledge of the risk factors for these infections as single entities, the inter-relationship between opportunistic fungii and CMV has not been comprehensively explored. Recent findings Both solid organ and stem cell transplant recipients who develop CMV invasive organ disease are at an increased risk of developing IFD, particularly aspergillosis and Pneumocystis pneumonia (PCP). Moreover, CMV viremia and recipient CMV serostatus also increased the risk of both early and late-onset IFD. Treatment related factors such as ganciclovir-induced neutropenia and host genetic Toll-like receptor (TLR) polymorphisms are likely to be contributory. Less is known about the relationship between CMV and IFD outside transplantation, such as in patients with hematological cancers or other chronic immunosuppressive conditions. Finally, few studies report on the relationship between CMV specific treatments or the viral/antigen kinetics and its influence on IFD management. Summary CMV infection is associated with increased risk of IFD in post-transplant recipients due to a number of overlapping and virus-specific risk factors. Better understanding of how CMV virus, its related treatment, CMV-induced immunosuppression and host genetic factors impact on IFD is warranted. Correspondence to Michelle K. Yong, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia. Tel: +61 3 8559 7991; fax: +61 3 8559 7999; e-mails: Michelle.Yong@unimelb.edu.au, michelle.yong@petermac.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Nanjo, Y., Newstead, M. W., Aoyagi, T., Zeng, X., Takahashi, K., Yu, F. S., Tateda, K., Standiford, T. J.

Legionella pneumophila (Lp) causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against Lp infection. Interleukin (IL)-36 cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused by Lp. Intratracheal (i.t.) administration of Lp induced the upregulation of both IL-36α and IL-36 mRNA and protein production in the lung. Compared to wild type (WT) mice, the i.t. administration of Lp to IL-36 receptor deficient (IL-36R-/-) mice resulted in increased mortality, a delay in lung bacterial clearance, increased Lp dissemination to extrapulmonary organs and impaired glucose homeostasis, as compared to Lp infected WT mice. Impaired lung bacterial clearance in IL-36R-/- mice was associated with significantly reduced accumulation of inflammatory cells and decreased production of pro-inflammatory cytokines and chemokines. Ex-vivo, reduced expression of co-stimulatory molecules and impaired M1 polarization was observed in alveolar macrophages isolated from infected IL-36R-/- mice as compared to macrophages from WT mice. While Lp-induced mortality in IL-36α or IL-36 deficient mice was not different that WT animals, antibody-mediated neutralization of IL-36 in IL-36α-/- mice resulted in mortality similar to that observed in IL-36R-/- mice, indicating redundant and overlapping roles for these cytokines in experimental murine Lp pneumonia.

Machuca, J., Lopez-Cerero, L., Fernandez-Cuenca, F., Mora-Navas, L., Mediavilla-Gradolph, C., LOpez-RodrIguez, I., Pascual, A.

The aim of this study was to characterize the population structure of 56 OXA-48-like-producing K. pneumoniae isolates, as well as ESBLs and carbapenemases genes, recovered in 2014 and 2015 from 16 hospitals in southern Spain. XbaI PFGE and MLST were performed to assess clonal relatedness. Representative isolates belonging to OXA-48-like-producing and CTX-M-15-co-producing pulsotypes were selected for characterization of blaOXA-48-like- and blaCTX-M-15-carrying plasmids by PCR-based replicon typing, IncF subtyping, WGS analysis and typing of Tn1999 structures. Forty-three (77%) OXA-48-producing isolates were recovered from clinical samples and 13 from rectal swabs. All isolates showed ertapenem MIC values ≥ 1 mg/L, although 70% remained susceptible to imipenem and meropenem. Forty-nine isolates (88%) produced OXA-48, 5 produced OXA-245, and 2 produced OXA-181. Twenty-eight different pulsotypes (5 detected in more than one hospital) and 16 sequencetypes were found. The most prevalent clones were ST15 (29 isolates, 52%) and ST11 (7 isolates, 13%). Forty-five (80%) isolates were also blaCTX-M-15 carriers. The blaCTX-M-15 gene was mostly (82%) located on IncR plasmids, although ST15 and ST11 isolates also carried this gene on IncF plasmids. The composite transposon variant Tn1999.2-like was the most frequent. Among ST15 and ST11 isolates, different transposon variants were observed. The blaOXA-48 gene was mainly located on IncL plasmids, although IncM plasmids were also observed. The spread of OXA-48-like-producing K. pneumoniae in southern Spain is mainly due to ST15 and ST11 clones. Variation within clonal lineages could indicate different acquisition events for both ESBL and carbapenemase traits.

Rasch, J., Ünal, C. M., Klages, A., Karsli, U., Heinsohn, N., Brouwer, R. M. H. J., Richter, M., Dellmann, A., Steinert, M.

The gamma-proteobacterium Legionella pneumophila is the causative agent of Legionnaires’ disease, an atypical pneumonia that manifests itself with severe lung damage. L. pneumophila, a common inhabitant of fresh water environments, replicates in free-living amoebae, and persists in biofilms in natural and man-made water systems. Its environmental versatility is reflected in its ability to survive and grow within a broad temperature range as well as its capability to colonize and infect a wide range of hosts including protozoa and humans. Peptidyl-prolyl-cis/trans-isomerases (PPIases) are multifunctional proteins that mainly are involved in protein folding and secretion in bacteria. In L. pneumophila the surface associated PPIase Mip was shown to facilitate the establishment of the intracellular infection cycle in its early stages. The cytoplasmic PpiB was shown to promote cold tolerance. Here, we set out to analyze the interrelationship of these two relevant PPIases in the context of environmental fitness and infection. We demonstrate that the PPIases Mip and PpiB are important for surfactant dependent sliding motility, and adaptation to suboptimal temperatures, features that contribute to the environmental fitness of L. pneumophila. Furthermore, they contribute to the infection of the natural host Acanthamoeba castellanii as well as human macrophages and human explanted lung tissue. These effects were additive in case of sliding motility, or synergistic in case of temperature tolerance and infection as assessed by the behavior of the double mutant. Accordingly, we propose that Mip and PpiB are virulence modulators of L. pneumophila with compensatory action and pleiotropic effects.

Abstract Background Respiratory tract infections (RTIs) are the most common illness in children, and rapid diagnosis is required for the optimal management of RTIs, especially severe infections. Methods Nasopharyngeal swab or sputum specimens were collected from children aged 19 days to 15 years who were admitted to a hospital in Shanghai and diagnosed with RTIs. The specimens were tested with the FilmArray Respiratory Panel, a multiplex PCR assay that detects 16 viruses, Mycoplasma pneumoniae (M. pneumoniae), Bordetella pertussis (B. pertussis) and Chlamydophila pneumoniae (C. pneumoniae). Results Among the 775 children studied, 626 (80.8%, 626/775) tested positive for at least one organism, and multiple organisms were detected in 198 (25.5%). Rhinoviruses/enteroviruses (25.5%, 198/775) were detected most often, followed by respiratory syncytial virus (19.5%, 151/775), parainfluenza virus 3 (14.8%, 115/775), influenza A or B (10.9%), adenovirus (10.8%), M. pneumoniae (10.6%) and B. pertussis (6.3%). The prevalence of organisms differed by age, and most of the viruses were more common in winter. Of the 140 children suspected of having pertussis, 35.0% (49/140) tested positive for B. pertussis. Conclusions FilmArray RP allows the rapid simultaneous detection of a wide number of respiratory organisms, with limited hands-on time, in Chinese pediatric patients with RTIs.

Haleem, K. S., Ali, Y. M., Yesilkaya, H., Kohler, T., Hammerschmidt, S., Andrew, P. W., Schwaeble, W. J., Lynch, N. J.

Complement is a critical component of antimicrobial immunity. Various complement regulatory proteins prevent host cells from being attacked. Many pathogens have acquired the ability to sequester complement regulators from host plasma to evade complement attack. Here we describe how Streptococcus pneumoniae adopts a strategy to prevent the formation of the C3 convertase, C4bC2a, by the rapid conversion of surface bound C4b and iC4b into C4dg, which remains bound to the bacterial surface but no longer forms a convertase complex. Non-capsular virulence factors on the pneumococcus are thought to facilitate this process by sequestering C4b-binding protein (C4BP) from host plasma.When S. pneumoniae D39 was opsonised with human serum, the larger C4 activation products, C4b and iC4b, were undetectable, but the bacteria were liberally decorated with C4dg and C4BP. With targeted deletions of either PspA, or PspC, C4BP deposition was markedly reduced and there was a corresponding reduction in C4dg, and an increase in the deposition C4b and iC4b. The effect was greatest when PspA and PspC were both knocked out. Infection experiments in mice indicated that the deletion PspA and/or PspC resulted in the loss of bacterial pathogenicity. Recombinant PspA and PspC both bound serum C4BP, and both led to increased C4b and reduced C4dg deposition on S. pneumoniae D39. We conclude that PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b.ImportanceStreptococcus pneumoniae (the pneumococcus) causes pneumonia, septicemia and meningitis, claiming for more than a million lives every year. In common with many other pathogens, the pneumococcus has evolved mechanisms to avoid attack by the human immune system. Complement activation is a part of the immune response to pneumococcal infection. When complement is activated the pathogen becomes coated in complement proteins, chiefly C4b and C3b, which target it for clearance by phagocytes. The pneumococcal surface proteins PspA and PspC are known to inhibit the host complement system.Using pneumococci deficient in PspA and PspC, and recombinant forms of both proteins, we demonstrate that PspA and PspC sequester a host complement regulatory protein called C4BP. The physiological role of C4BP is to facilitate the breakdown of complement C4b. By recruiting C4BP to the bacterial surface, the pneumococcus accelerates the breakdown of C4b, thus helping it to avoid phagocytosis…

Coleman Kishamawe, Susan F. Rumisha, Irene R. Mremi, Veneranda M. Bwana, Mercy G. Chiduo, Isolide S. Massawe, Leonard E.G. Mboera

Abstract Objective To determine the causes, patterns and trends of respiratory diseases‐related deaths in hospitals of Tanzania 2006‐2015. Methods Retrospective study involving 39 hospitals. Medical records of patients who died in hospital were retrieved, reviewed and analysed. Sources of data were hospital admission registers, death registers, and International Classification of Diseases report forms. Information on demographic characteristics, date of death, the immediate underlying cause of death and co‐morbid conditions was collected. Results Of the 247,976 deaths reported during the 10‐year period, respiratory diseases accounted for 12.92% (n=32,042). The majority of the respiratory mortality were reported among males (55.9%). Overall median age at death was 31 years with an interquartile range (IQR) of 1‐47. Median age at death was significantly higher among males (35 years) than females (28 years) (p