Publications

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.

[This corrects the article DOI: 10.1371/journal.ppat.1002924.].

BACKGROUND

Acute kidney injury (AKI), which is common among HIV-positive individuals, may contribute to the excess burden of chronic kidney disease (CKD) in this patient population; however, conventional clinical methods to detect AKI do not capture kidney injury sufficiently early to prevent irreversible damage. Further, large observational and interventional studies of AKI generally exclude HIV-positive persons in spite of their disproportionate risk.

METHODS

The Predictors of Acute Renal Injury Study (PARIS) is a prospective observational cohort study among HIV-positive individuals established to determine the ability of candidate kidney injury biomarkers to predict future hospitalized clinical AKI, to characterize hospitalized subclinical AKI, and to discern the risk of progressive kidney disease following subclinical and clinical AKI. Among the candidate kidney injury markers, we will select the most promising to translate into a clinically viable, multiplex panel of urinary biomarkers which we will integrate with clinical factors to develop a model prognostic of risks for AKI and subsequent kidney function decline. This study has a targeted enrollment of 2000 participants. The overall follow-up of participants consists of two phases: 1) a 5-year active follow-up phase which involves serial evaluations at enrollment, annual clinic visits, and among participants who are hospitalized during this period, an evaluation at index hospitalization and 3 and 12 months post-hospitalization; and 2) a subsequent passive follow-up phase for the duration that the participant receives medical care at The Johns Hopkins Hospital.

DISCUSSIONS

This study will serve as an important resource for future studies of AKI by establishing a repository with both ambulatory and inpatient biospecimens, a resource that is currently lacking in existing HIV clinical cohorts and studies of AKI. Upon completion of this study, the resulting prognostic model which will incorporate results from the multiplex HIV-AKI Risk Pane could serve as a pharmacodynamic endpoint for early phase therapeutic candidates for AKI.