Clark D. Russell

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia

This is the first time a comprehensive, multipathogen, quantitative and qualitative molecular approach for respiratory bacteria and viruses has been compared with traditional diagnostic methods on a large hospitalized pneumonia cohort, with estimation of potential effects on antibiotic prescribing.

The role of pro-resolution lipid mediators in infectious disease

Inflammation is an essential host defence against infection, but can be damaging when excessive. Resolution of inflammation is an active process, and the pro‐resolution effects of lipoxins, resolvins and protectins have received significant interest. Here, we review emerging data on the role of these lipid mediators in infectious disease. Lipoxins influence host control of Mycobacterium tuberculosis, Toxoplasma gondii, Trypanosoma cruzi and Plasmodium berghei cerebral malaria in mice. Their effects are protective in toxoplasmosis, T. cruzi infection and cerebral malaria but detrimental in tuberculosis; related to the balance between pathogen‐control and excessive immune response. Topical lipoxin abrogates the tissue damage seen in a rabbit model of Porphyromonas gingivalis periodontitis. The increased virulence of H5N1 influenza A virus in mice correlates with reduced expression of SOCS2, required to mediate the effects of lipoxin. Mice unable to synthesize lipoxin suffer increased lung pathology during respiratory syncytial virus infection. Protectin suppresses influenza A virus replication in vitro and increases survival in a mouse model of severe influenza infection. Resolvins were investigated in a number of animal models of systemic bacterial infection, and were found to enhance phagocytic clearance of bacteria, reduce inflammation severity, promote neutrophil apoptosis, modulate neutrophil chemotaxis and importantly, reduce mortality. Interestingly, resolvin also enhances the antibacterial effect of ciprofloxacin and vancomycin. Topical resolvin application reduces the severity of herpes simplex virus ocular infection in mice. If the effects of these mediators translate from pre‐clinical studies into successful clinical trials, they represent promising new strategies in managing infectious disease.

Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010

There is growing recognition of the clinical importance of non-tuberculous mycobacteria (NTM), a group of versatile opportunistic bacterial pathogens. We describe the characteristics of NTM isolates in Scotland over an 11-year period using data held by the Scottish Mycobacteria Reference Laboratory. American Thoracic Society microbiological criteria were used to evaluate the clinical significance of isolates. Data presented include analysis of trends across time, species/body site associations, gender and age differences, geographical variations and the association between cystic fibrosis and Mycobacterium abscessus. We emphasise the need for standardised reporting criteria for NTM isolates to ensure optimal surveillance of NTM disease.

Twelve tips for teachers to encourage student engagement in academic medicine

Background: Recruitment of trainees into clinical academic medicine remains an area of concern across the globe, with clinical academics making up a dwindling proportion of the medical workforce. To date, few approaches have emphasised early medical student research involvement as a solution to the decline of the clinician-scientist. Aim and method: We identify 12 tips that all medical teachers can adopt to foster medical student participation in research and encourage student engagement with academic aspects of medicine throughout their time as an undergraduate. These recommendations are based on a comprehensive review of the international literature and our personal experience of research-focussed interventions and activities as medical students. Conclusion: Through these 12 tips, we provide a practical framework for enhancing medical student exposure to research at medical school. This has the potential to inspire and maintain student interest in the varied role of the clinical academic and could contribute to reversing the downward trend that has occurred in this field over recent times.

Development of two real-time multiplex PCR assays for the detection and quantification of eight key bacterial pathogens in lower respiratory tract infections

The frequent lack of a positive and timely microbiological diagnosis in patients with lower respiratory tract infection (LRTI) is an important obstacle to antimicrobial stewardship. Patients are typically prescribed broad-spectrum empirical antibiotics while microbiology results are awaited, but, because these are often slow, negative, or inconclusive, de-escalation to narrow-spectrum agents rarely occurs in clinical practice. The aim of this study was to develop and evaluate two multiplex real-time PCR assays for the sensitive detection and accurate quantification of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We found that all eight bacterial targets could be reliably quantified from sputum specimens down to a concentration of 100 CFUs/reaction (8333 CFUs/mL). Furthermore, all 249 positive control isolates were correctly detected with our assay, demonstrating effectiveness on both reference strains and local clinical isolates. The specificity was 98% on a panel of nearly 100 negative control isolates. Bacterial load was quantified accurately when three bacterial targets were present in mixtures of varying concentrations, mimicking likely clinical scenarios in LRTI. Concordance with culture was 100% for culture-positive sputum specimens, and 90% for bronchoalveolar lavage fluid specimens, and additional culture-negative bacterial infections were detected and quantified. In conclusion, a quantitative molecular test for eight key bacterial causes of LRTI has the potential to provide a more sensitive decision-making tool, closer to the time-point of patient admission than current standard methods. This should facilitate de-escalation from broad-spectrum to narrow-spectrum antibiotics, substantially improving patient management and supporting efforts to curtail inappropriate antibiotic use.

Microbiological characteristics of acute osteoarticular infections in children

This study aimed to describe the microbiological characteristics of acute septic arthritis (SA) and osteomyelitis (OM) in children. Cases of children (0-15 years) with SA/OM were identified through a retrospective search of hospital discharge codes over a six-year period. In addition, a systematic literature search and meta-analysis of studies reporting culture results of children with SA/OM was performed. In our retrospective chart review, we identified 65 cases of OM and 46 cases of SA. The most frequently cultured organisms in both conditions were Gram-positive cocci, primarily Staphylococcus aureus. On admission, most patients had a normal white blood cell count (WCC) but elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR). Bacteraemia was associated with a longer mean length of hospitalization for both infections. Considering our results and the meta-analysis, we found low rates of culture-positivity in cases of clinically confirmed infection. In SA, articular fluid was culture-positive in 42.49% [95% confidence interval (CI) 28.39-57.23]. In OM, intra-operative samples were culture-positive in 52.65% (95% CI 30.54-74.22). Bacteraemia was detected in 23.91% (95% CI 8.40-44.24) of children with SA and 21.48% (95% CI 10.89-34.47) with OM. Despite appropriate sampling, a positive microbiological diagnosis is often lacking in paediatric acute osteoarticular infection using standard culture-based methods. This highlights the need for validation and use of more sensitive diagnostic methods, such as PCR.

The Human Immune Response to Respiratory Syncytial Virus Infection

SUMMARY Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

The Role of Interferon-λ Locus Polymorphisms in Hepatitis C and Other Infectious Diseases

Since its discovery in 2003, the type III interferon-λ (IFN-λ) family has been found to contribute significantly to the host response to infection. Whilst IFN-λ shares many features with type I IFN induction and signalling pathways, the tissue-specific restricted expression of its receptor, IL28RA, makes IFN-λ a major mediator of host innate immunity in tissues and organs with a high epithelial cell content. Host susceptibility and responses to infection are known to be heterogeneous, and the identification of common genetic variants linked to disease outcome by genome-wide association studies (GWAS) has underscored the significance of host polymorphisms in responses to infection. Several such GWAS have highlighted the IFN-λ locus on chromosome 19q13 as an area of genetic variation significantly associated with hepatitis C virus (HCV) infection, and the rs12979860 genotype can be used in clinical practice as a biomarker for predicting a successful response to treatment with pegylated IFN and ribavarin. Here, we discuss IFN-λ genetic polymorphisms and their role in HCV and other infectious diseases as well as their potential impact on clinical diagnostics, patient stratification and therapy. Finally, the broader role of IFN-λ in the immunopathogenesis of non-infectious inflammatory diseases is considered.

Interferon Lambda Genetic Polymorphisms and Viral Infection: The Tip of the Iceberg?

Pathogen-host interaction studies have demonstrated the importance of host factors in the pathogenesis of infectious disease. An emerging theme is that polymorphisms in the genes encoding these factors can influence the host response to infection and the course of disease. Genetic variation affecting interferon lambda (IFN-λ) expression is now known to influence the outcome of both hepatitis C virus and herpes simplex virus type 1 infection in humans. IFN-λ is expressed at higher levels in organs with high epithelial cell content such as the respiratory and gastrointestinal tracts. Interestingly, data from animal models show that IFN-λ contributes to host control of viruses infecting these sites, including influenza A virus, severe acute respiratory syndrome coronavirus, and rotavirus. Furthermore, defective IFN-λ production by humans with asthma impairs the control of rhinovirus infection. We hypothesize that genetic variation of IFN-λ could potentially influence the course of disease during infection with many viruses that infect epithelial cells.

Perceived barriers to research in undergraduate medicine

Dear SirThe 2005 Walport report described the ‘perilous state of academic medicine in the UK’ and recommended that the attractions of research and academic medicine should be better promoted to med...