Publications

Sepsis remains a highly lethal entity resulting in more than 200 000 deaths in the USA each year. The in-hospital mortality approaches 30% despite advances in critical care during the last several decades. The direct health care costs in the USA exceed $24 billion dollars annually and continue to escalate each year especially as the population ages. The Surviving Sepsis Campaign published their initial clinical practice guidelines for the management of severe sepsis and septic shock in 2004. Updated versions were published in 2008, 2012 and most recently in 2016 following the convening of the Third International Consensus Definitions Task Force. This task force was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine to address prior criticisms of the multiple definitions used clinically for sepsis-related illnesses. In the 2016 guidelines, sepsis is redefined by the taskforce as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In addition to using the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score to more rapidly identify patients with sepsis, the task force also proposed a novel scoring system to rapidly screen for patients outside the ICU who are at risk of developing sepsis: the 'quickSOFA' (qSOFA) score. To date, the largest reductions in mortality have been associated with early identification of sepsis, initiation of a 3-hour care bundle and rapid administration of broad-spectrum antibiotics. The lack of progress in mortality reduction in sepsis treatment despite extraordinary investment of research resources underscores the variability in patients with sepsis. No single solution is likely to be universally beneficial, and sepsis continues to be an entity that should receive high priority for the development of precision health approaches for treatment.

HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.

Microbiome studies show altered microbiota in head and neck squamous cell carcinoma (HNSCC), both in terms of taxonomic composition and metabolic capacity. These studies utilized a traditional bioinformatics methodology, which allows for accurate taxonomic assignment down to the genus level, but cannot accurately resolve species level membership. We applied Resphera Insight, a high-resolution methodology for 16S rRNA taxonomic assignment that is able to provide species-level context in its assignments of 16S rRNA next generation sequencing (NGS) data. Resphera Insight applied to saliva samples from HNSCC patients and healthy controls led to the discovery that a subset of HNSCC saliva samples is significantly enriched with commensal species from the vaginal flora, including (710x higher in saliva) and (52x higher in saliva). These species were not observed in normal saliva from Johns Hopkins patients, nor in 16S rRNA NGS saliva samples from the Human Microbiome Project (HMP). Interestingly, both species were only observed in saliva from Human Papilloma Virus (HPV) positive and HPV negative oropharyngeal cancer patients. We confirmed the representation of both species in HMP data obtained from mid-vagina (n=128) and vaginal introitus (n=121) samples. Resphera Insight also led to the discovery that , an oral cavity flora commensal bacterium linked to colon cancer, is enriched (600x higher) in saliva from a subset of HNSCC patients with advanced tumors stages. Together, these high-resolution analyses on 583 samples suggest a possible role for bacterial species in the therapeutic outcome of HPV positive and HPV negative HNSCC patients.