The Role of 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in Management of Nocardiosis: A Retrospective Study and Review of the Literature.

INTRODUCTION: 18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is a well-established tool for managing metastatic infections. Nocardiosis, a primarily pulmonary infection, disseminates at high rates. Routine imaging includes chest CT and brain imaging. We examined the use of FDG-PET/CT in nocardiosis and assessed its contribution to diagnosis and management. METHODS: A retrospective study in two tertiary medical centers during 2011-2020. Individuals with nocardiosis for whom FDG-PET/CT was implemented for any reason were included and their medical records were reviewed. A board-certified nuclear medicine physician independently reviewed all scans. Additionally, a systematic review was conducted according to the PRISMA guidelines, to extract data from publications reporting FDG-PET/CT use for the management of nocardiosis. RESULTS: FDG-PET/CT contributed to the management of all seven patients who met inclusion criteria. It assisted in ruling out an underlying malignancy (29%, 2/7); establishing a wide infection extent (57%, 4/7); and affecting decisions regarding treatment (57%, 4/7), including drug regimen, oral step-down, and duration of therapy. We identified 20 published case reports on this topic. In 80% (16/20), FDG-PET/CT contributed to the management of nocardiosis similar to our study. In addition, in most of the literature cases, FDG-PET/CT guided the diagnostic biopsy. CONCLUSION: FDG-PET/CT is valuable in the diagnosis and management of individuals with nocardiosis. The contribution of incorporating FDG-PET/CT to the management of individuals with nocardiosis and its role in monitoring treatment response and shortening treatment duration should be evaluated in prospective studies.

Drivers of within-host genetic diversity in acute infections of viruses.

Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.

Clinical correlates of nocardiosis.

Nocardia is an opportunistic pathogen that most frequently affects the lungs. Evidence is limited regarding the risk factors for nocardiosis. The current study assessed clinical correlates of nocardiosis. A retrospective study was conducted based on medical records of consecutive adult patients (N = 60) with nocardiosis hospitalized during 2007-2018 at a tertiary hospital in central Israel. A matched comparison group of 120 patients was randomly selected among hospitalized patients with community-acquired pneumonia. Multivariable conditional logistic regression models were fitted. Immunosuppressive pharmacotherapy was positively associated with nocardiosis (matched odds ratio [OR] 4.40, 95% confidence interval [CI] 2.25-8.62, p < 0.001), particularly corticosteroid therapy (matched OR 4.69, 95% CI 2.45-8.99, p < 0.001). Systemic corticosteroid therapy was strongly associated with pulmonary nocardiosis (matched OR 5.90, 95% CI 2.75-12.66, p < 0.001). The positive association between solid organ transplantation and nocardiosis was attenuated following adjustment for systemic corticosteroids in a multivariable model. The association between corticosteroid therapy and nocardiosis appeared stronger in patients with chronic pulmonary disease (OR 5.74, 95% CI 2.75-12.66, p < 0.001) than in the pooled analysis of all nocardiosis cases. In conclusion, corticosteroid therapy was strongly correlated with nocardiosis, particularly among individuals with chronic pulmonary disease and in pulmonary nocardiosis.

Nocardia colonization in contrast to nocardiosis: a comparison of patients' clinical characteristics.

Information on Nocardia colonization of the lower respiratory tract is scarce. The current study is aimed at comparing clinical characteristics between individuals with Nocardia colonization and those with nocardiosis. All patients with Nocardia isolation between 2007 and 2018 at a tertiary hospital in Israel were included. Nocardia isolation was based on biochemical tests together with phenotypic susceptibility and resistance patterns until 2011 and on matrix-assisted laser desorption/ionization time-of-flight mass spectrometer from 2012. We defined nocardiosis as a clinically evident infection related to the isolation of the bacteria, which required antibiotic therapy. We defined colonization as Nocardia isolation with no clinical evidence of disease. The medical charts of all included individuals were independently reviewed by an infectious disease specialist to ensure adequate classification. Logistic regression models were fitted to compare clinical characteristics between the groups. Fifteen (20%) of the 75 Nocardia isolations met the criteria for colonization. Of those, 13 (87%) had background illnesses. Having a chronic pulmonary disease was associated with increased likelihood of Nocardia colonization, in contrast to nocardiosis (adjusted odds ratio [OR] 4.06, 95% confidence interval [CI] 1.06-15.48, p = 0.040), while an inverse association was found with corticosteroid therapy (adjusted OR 0.21, 95% CI 0.06-0.74, p = 0.015). Nocardia colonization of the lower respiratory tract accounts for a substantial proportion of all Nocardia isolations. Individuals colonized with Nocardia typically have chronic pulmonary disease and are less frequently treated with corticosteroid than patients with nocardiosis.

Pathogen receptor discovery with a microfluidic human membrane protein array.

The discovery of how a pathogen invades a cell requires one to determine which host cell receptors are exploited. This determination is a challenging problem because the receptor is invariably a membrane protein, which represents an Achilles heel in proteomics. We have developed a universal platform for high-throughput expression and interaction studies of membrane proteins by creating a microfluidic-based comprehensive human membrane protein array (MPA). The MPA is, to our knowledge, the first of its kind and offers a powerful alternative to conventional proteomics by enabling the simultaneous study of 2,100 membrane proteins. We characterized direct interactions of a whole nonenveloped virus (simian virus 40), as well as those of the hepatitis delta enveloped virus large form antigen, with candidate host receptors expressed on the MPA. Selected newly discovered membrane protein-pathogen interactions were validated by conventional methods, demonstrating that the MPA is an important tool for cellular receptor discovery and for understanding pathogen tropism.

Microfluidic large scale integration of viral-host interaction analysis.

Viral-host interactions represent potential drug targets for novel antiviral strategies (Flisiak et al., Hepatology, 2008, 47, 817-26). Hence, it is important to establish an adequate platform for identifying and analyzing such interactions. In this review, we discuss bottlenecks in conventional protein-protein interaction methodologies and present the contribution of innovative microfluidic-based technologies towards a solution to these problems with respect to viral-host proteomics.

The life of an mRNA in space and time.

Nuclear transcribed genes produce mRNA transcripts destined to travel from the site of transcription to the cytoplasm for protein translation. Certain transcripts can be further localized to specific cytoplasmic regions. We examined the life cycle of a transcribed beta-actin mRNA throughout gene expression and localization, in a cell system that allows the in vivo detection of the gene locus, the transcribed mRNAs and the cytoplasmic beta-actin protein that integrates into the actin cytoskeleton. Quantification showed that RNA polymerase II elongation progressed at a rate of 3.3 kb/minute and that transactivator binding to the promoter was transient (40 seconds), and demonstrated the unique spatial structure of the coding and non-coding regions of the integrated gene within the transcription site. The rates of gene induction were measured during interphase and after mitosis, demonstrating that daughter cells were not synchronized in respect to transcription initiation of the studied gene. Comparison of the spatial and temporal kinetics of nucleoplasmic and cytoplasmic mRNA transport showed that the beta-actin-localization response initiates from the existing cytoplasmic mRNA pool and not from the newly synthesized transcripts arising after gene induction. It was also demonstrated that mechanisms of random movement were predominant in mediating the efficient translocation of mRNA in the eukaryotic cell.