Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis.

OBJECTIVE: CD16+ /CD163+ macrophages (MΦs) and microglia accumulate in the brains of patients with human immunodeficiency virus (HIV) encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia. Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE and HIV/noE, and HIV- controls. METHODS: Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+ , CD16+ , or CD68+ MΦs/microglia per case, using terminal continuation RNA amplification and a custom-designed array platform. RESULTS: Several classes of microglial transcripts in HIVE and HIV/noE were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors were reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE. INTERPRETATION: Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as to ascertain alterations in specific pathways, genes, and potentially, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. Ann Neurol 2018;83:406-417.

Exogenous reinfection of tuberculosis in a low-burden area.

PURPOSE: Recurrence of tuberculosis (TB) can be the consequence of relapse or exogenous reinfection. The study aimed to assess the factors associated with exogenous TB reinfection. METHODS: Prospective cohort study based on the TB database, maintained at the Division of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy). Time period: 1995-2010. INCLUSION CRITERIA: (1) ≥2 episodes of culture-confirmed TB; (2) cure of the first episode of TB; (3) availability of one Mycobacterium tuberculosis isolate for each episode. Genotyping of the M. tuberculosis strains to differentiate relapse and exogenous reinfection. Logistic regression analysis was used to assess the influence of risk factors on exogenous reinfections. RESULT: Of the 4682 patients with TB, 83 were included. Of these, exogenous reinfection was diagnosed in 19 (23 %). It was independently associated with absence of multidrug resistance at the first episode [0, 10 (0.01-0.95), p = 0.045] and with prolonged interval between the first TB episode and its recurrence [7.38 (1.92-28.32) p = 0.004]. However, TB relapses occurred until 4 years after the first episode. The risk associated with being foreign born, extrapulmonary site of TB, and HIV infection was not statistically significant. In the relapse and re-infection cohort, one-third of the patients showed a worsened drug resistance profile during the recurrent TB episode. CONCLUSIONS: Exogenous TB reinfections have been documented in low endemic areas, such as Italy. A causal association with HIV infection could not be confirmed. Relapses and exogenous reinfections shared an augmented risk of multidrug resistance development, frequently requiring the use of second-line anti-TB regimens.

Mycobacterium tuberculosis Beijing family: analysis of the epidemiological and clinical factors associated with an emerging lineage in the urban area of Milan.

The Mycobacterium tuberculosis Beijing genotype raises major concern because of global spreading, hyper-virulence and association with multi-drug resistance (MDR). The aims of the study were to evaluate role of Beijing family in the epidemiological setting of Milan and to identify predictors associated with the spreading of this lineage. Overall 3830TB cases were included. Beijing family accounted for 100 isolates (2.6%). Prevalence grew from 1.7% to 5.4% in the period 1996-2009. Foreign origin increased significantly the risk of having a Beijing strain: the greatest risk was observed among patients coming either from China [AOR=57.7, 95%CI (26.3-126.8)] or from Former Soviet countries [AOR=33.9, 95%CI (12.8-99.6)]. Also MDR was independently associated with Beijing family [AOR=2.7, 95%CI (1.3-5.8)], whereas male gender and younger age only approximated the statistical significance [p 0.051 and p 0.099, respectively]. However, the percentage of cases attributable to MDR strains decreased over time, both in the Beijing group and in the non-Beijing group. 97 isolates were grouped in 37 sub-lineages: MT11, MT33 were predominant. Beijing family is an emerging lineage in Milan. Origin from countries like China and Ukraine and MDR are significantly associated with Beijing. The broad range of the sub-lineages reflects the recent dynamics of the migration flows to our area. This scenario can prelude to a constant increase in the spreading of Beijing strains in the near future.

[Recurrent tuberculosis: relapse or reinfection?]. / La tubercolosi ricorrente: recidiva o reinfezione esogena?

Recurrent tuberculosis (TB) is an issue that makes worldwide eradication of the disease difficult, especially in countries with a high incidence of TB. Recurrent TB may be due to relapse of the original episode or to an exogenous reinfection caused by a different strain of Mycobacterium tuberculosis. We performed a meta-analysis of selected studies on recurrent TB from 2000 to 2013, adopting molecular genotyping to discriminate between exogenous reinfection and relapses, in order to specifically evaluate the role of HIV infection in the origin of recurrence. Comparison among the studies was limited by the population heterogeneity of the different studies in terms of epidemiology, health status, and diagnostic and therapeutic approach. However, exogenous reinfections are more common in high-burden countries, where HIV infection plays a major role in increasing the risk of a new infection. In contrast, this finding was not confirmed in low-burden countries. Vice versa, globally recognized factors for TB relapse were low compliance to anti-tuberculous treatment, multidrug resistance and persistence of cavitations in the lung parenchyma. The role of other factors like social conditions (immigration, homelessness, working conditions), co-morbidities (silicosis), and characteristics of anti-TB treatment is still controversial.

Influence of Hospitalization upon Diagnosis on the Risk of Tuberculosis Clustering.

SETTING: Culture-positive tuberculosis (TB) diagnosed in the metropolitan area of Milan (Italy) over a 5-year period (1995-1999). OBJECTIVE: To assess the impact of short-course hospitalization upon diagnosis on the overall risk of TB clustering. DESIGN: Restriction fragment length polymorphism profiles with a similarity of 100% defined a cluster. Uni- and multivariable logistic regression models were performed to assess factors associated with clustering. RESULTS: Among 1139 patients, 392 (34.4%) were hospitalized before or soon after diagnosis, 405 (35.6%) received domiciliary treatment since the diagnosis and 392 (30%) had no information about initial clinical management. One hundred fifteen molecular clusters involving 363 patients were identified. Using multivariable analysis, hospitalization was not significantly associated with clustering (OR 1.06, 95%CI 0.75-1.50, p=0.575). Subjects aged >65 years old (OR 0.60; 95CI%:0.37-0.95; p=0.016) and non-Italian born patients (OR 0.56; 95%CI:0.41-0.76; p<0.001) were running a lower risk of clustering. Conversely, HIV co-infected patients (OR 1.88, 95%CI:1.20-2.95, p=0.006) and those with MDR TB (OR 2.50, 95%CI:1.46-4.25, p=0.001) were significantly more likely to be involved in clusters. CONCLUSION: In our cohort, domiciliary treatment was not associated with TB clustering. Expanding domiciliary treatment upon diagnosis appears as an advisable measure to reduce unnecessary costs for the health care system.