Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism.

Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug or more specific efflux pump inhibitors to standard antitubercular therapy should shorten the duration of curative treatment.

Destructive Processes and Fibrotic Complications in the Liver of Mice with BSG-Induced Granulomatosis Treated with Anti-Tuberculous Drugs.

Three months after infection with Mycobacterium tuberculosis (MBT) from BCG vaccine, male BALB/с mice were treated with isonicotinic acid hydrazide, dextrazide (oxidized dextran), and liposome-encapsulated dextrazide intraperitoneally or in inhalations in a dose of 14 mg/kg (calculated for isoniazid) twice a week for 6 months. All these drugs exhibit different antimycobacterial efficiency. In the liver parenchyma, an up to 5-fold decrease in the number of destructed hepatocytes was observed depending on the efficiency of treatment. No destructive processes were observed in granulomas. Type I and III collagens were revealed around the granulomas; their content in the liver parenchyma was negligible. TNFα, IL-6, MMP-1, ТIMP1 were expressed only by granuloma macrophages. As the number of damaged hepatocytes and size of inflammatory infiltrates in the liver parenchyma decreased, the content of both types of collagen decreased. No evidence of hepatotoxicity of MBT degradation products in macrophages in vivo was obtained; the assumption that fibrotic complications are only the post-destruction process was not confirmed. Fibrotic complications are supposed to be an "excessive" systemic nonspecific adaptive process aimed at the maintenance the so-called structural homeostasis initiated by activated М2-macrophages in granulomas.

Liposomes with Water as a pH-Responsive Functionality for Targeting of Acidic Tumor and Infection Sites.

A lipid named DCPA was synthesized under microwave-assisted heating. DCPA possesses a pyridine betaine, hydrophilic group that can be complexed with water through hydrogen bonding (DCPA-H2 O). DCPA-H2 O liposomes became protonated relatively fast already at pH<6.8, due to the high HOMO binding energy of DCPA-H2 O. In murine models, DCPA-H2 O liposomes had longer blood circulation times than natural DPPC or cationic DCPM liposomes, while after tail-vein injection DCPA-H2 O liposomes targeted faster to solid tumors and intra-abdominal infectious biofilms. Therapeutic efficacy in a murine, infected wound-healing model of tail-vein injected ciprofloxacin-loaded DCPA-H2 O liposomes exceeded the ones of clinically applied ciprofloxacin as well as of ciprofloxacin-loaded DPPC or DCPM liposomes.

M1 macrophage dependent-p53 regulates the intracellular survival of mycobacteria.

Tumor suppressor p53 is not only affects immune responses but also contributes to antibacterial activity. However, its bactericidal function during mycobacterial infection remains unclear. In this study, we found that the p53-deficient macrophages failed to control Mycobacterium tuberculosis (Mtb), manifested as a lower apoptotic cell death rate and enhanced intracellular survival. The expression levels of p53 during Mtb infection were stronger in M1 macrophages than in M2 macrophages. The TLR2/JNK signaling pathway plays an essential role in the modulation of M1 macrophage polarization upon Mtb infection. It facilitates p53-mediated apoptosis through the production of reactive oxygen species, nitric oxide and inflammatory cytokines in Mtb-infected M1 macrophages. In addition, nutlin-3 effectively abrogated the intracellular survival of mycobacteria in both TB patients and healthy controls after H37Ra infection for 24 h, indicating that the enhancement of p53 production effectively suppressed the intracellular survival of Mtb in hosts. These results suggest that p53 can be a new therapeutic target for TB therapy.

The impact on incident tuberculosis by kidney function impairment status: analysis of severity relationship.

BACKGROUND: The risk of tuberculosis (TB) in patients with impaired kidney function remains unclear by different stages of renal function impairment. METHODS: We retrospectively recruited all patients with kidney function in a tertiary-care referral center from January 2008 to December 2013 and followed them till December 2016. We defined the primary outcome as active TB development and analyzed the impact of kidney function impairment. RESULTS: During the study period, a total of 289,579 patients were enrolled for analysis, and of them, 1012 patients had active TB events in an average of 4.13 years of follow-up. According to kidney function impairment, the incidence rate of TB was similar in patients with no chronic kidney disease (CKD) or stage 1 and stage 2, and it increased apparently at stage 3a (167.68 per 100,000 person-years) to stage 3b, stage 4 and stage 5 (229.25, 304.95 and 349.29 per 100,000 person-years, respectively). In a Cox proportional hazard regression model, the dose response of TB risk among different stages of kidney function impairment increased significantly from CKD stage 3a to stage 5. Patients with long-term dialysis had a hazard ratio of 2.041 (1.092-3.815, p = 0.0254), which is similar to that of stage 4 CKD but lower than that of stage 5. CONCLUSION: In patients with impaired kidney function, the risk of TB increases from CKD stage 3, and in stage 5, the risk is even higher than that of those receiving dialysis. Further strategies of TB control need to consider this high-risk group.

Cancer incidence attributable to tuberculosis in 2015: global, regional, and national estimates.

BACKGROUND: Tuberculosis is associated with increased risk of cancer. However, the impact of tuberculosis on global cancer burden is unknown. METHODS: We performed random-effects meta-analyses and meta-regressions of studies reporting the association between tuberculosis and cancer risks by searching PubMed, Web of Science, Embase, Cochrane library, and CINAHL from inception to 1 June 2019. Population attributable fractions (PAFs) of cancer incidence attributable to tuberculosis were calculated using relative risks from our meta-analyses and tuberculosis prevalence data from Global Health Data Exchange by age, sex, and country. The study has been registered with PROSPERO (CRD42016050691). RESULTS: Fourty nine studies with 52,480 cancer cases met pre-specified inclusion criteria. Tuberculosis was associated with head and neck cancer (RR 2.64[95% CI 2.00-3.48]), hepatobiliary cancer (2.43[1.82-3.25]), Hodgkin's lymphoma (2.19[1.62-2.97]), lung cancer (1.69[1.46-1.95]), gastrointestinal cancer (1.62[1.26-2.08]), non-Hodgkin's lymphoma (1.61[1.34-1.94]), pancreatic cancer (1.58[1.28-1.96]), leukaemia (1.55[1.25-1.93]), kidney and bladder cancer (1.54[1.21-1.97]), and ovarian cancer (1.43[1.04-1.97]). We estimated that 2.33%(1.14-3.81) or 381,035(187145-623,404) of global cancer incidences in 2015 were attributable to tuberculosis. The PAFs varied by Socio-demographic Index (SDI)-ranging from 1.28% (0.57-2.31%) in the high-SDI countries to 3.51% (1.84-5.42%) in the middle-SDI countries. Individually, China and India accounted for 47% of all tuberculosis-related cancer cases. CONCLUSIONS: Tuberculosis is associated with increased risk of cancer at ten sites. The burden of tuberculosis attributable cancer skewed towards lower resource countries. Research priorities are to better understand regional disparities and underlying mechanism linking tuberculosis and cancer development.

Breast tuberculosis in East London: A 13-year retrospective observational study.

SETTING: Breast tuberculosis (TB) is rare in Western Europe, and its diagnosis may be delayed through lack of awareness of presenting features. Our institution serves a large East London population with a high incidence of TB. OBJECTIVE: To characterize presenting features and avoidable diagnostic delay in breast TB patients. DESIGN: We conducted a 13-year retrospective study of breast TB patients treated at our institution including demographic, clinical, microbiology, and pathology data. RESULTS: Forty-seven cases were included; 44 (94%) were female, with a median age of 33 years (IQR 28.5-39.5). The main presenting feature was a breast lump in 41 cases (87%); which were predominantly solitary unilateral lesions (25, 61%) and frequently located in the upper outer quadrant (28, 68%). Where performed, Mycobacterium tuberculosis was cultured in 15/36 (42%) cases. Granulomata were present on biopsy or aspirate in 21 (47%) and 17 (36%) cases, respectively. The median duration between symptom onset and treatment was 20 weeks (IQR 15-30). Forty-six (98%) completed treatment successfully and one relapsed. CONCLUSION: A high index of suspicion for TB is required for individuals presenting with breast symptoms from countries where TB is endemic. Development of standardized pathways may improve detection and management of breast TB may reduce diagnostic delay.

The Rate of CD4 T Cell Entry into the Lungs during Mycobacterium tuberculosis Infection Is Determined by Partial and Opposing Effects of Multiple Chemokine Receptors.

The specific chemokine receptors utilized by Th1 cells to migrate into the lung during Mycobacterium tuberculosis infection are unknown. We previously showed in mice that CXCR3+ Th1 cells enter the lung parenchyma and suppress M. tuberculosis growth, while CX3CR1+ KLRG1+ Th1 cells accumulate in the lung vasculature and are nonprotective. Here we quantify the contributions of these chemokine receptors to the migration and entry rate of Th1 cells into M. tuberculosis-infected lungs using competitive adoptive transfer migration assays and mathematical modeling. We found that in 8.6 h half of M. tuberculosis-specific CD4 T cells migrate from the blood to the lung parenchyma. CXCR3 deficiency decreases the average rate of Th1 cell entry into the lung parenchyma by half, while CX3CR1 deficiency doubles it. KLRG1 blockade has no effect on Th1 cell lung migration. CCR2, CXCR5, and, to a lesser degree, CCR5 and CXCR6 also promote the entry of Th1 cells into the lungs of infected mice. Moreover, blockade of G-protein-coupled receptors with pertussis toxin treatment prior to transfer only partially inhibits T cell migration into the lungs. Thus, the fraction of Th1 cell input into the lungs during M. tuberculosis infection that is regulated by chemokine receptors likely reflects the cumulative effects of multiple chemokine receptors that mostly promote but that can also inhibit entry into the parenchyma.

Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis.

Immunological memory is the key biological process that makes vaccines possible. Although tuberculosis vaccines elicit protective immunity in animals, few provide durable protection. To understand why protection is transient, we evaluated the ability of memory CD4+ T cells to expand, differentiate, and control Mycobacterium tuberculosis. Both naïve and memory CD4+ T cells initially proliferated exponentially, and the accumulation of memory T cells in the lung correlated with early bacterial control. However, later during infection, memory CD4+ T cell proliferation was curtailed and no protection was observed. We show that memory CD4+ T cells are first activated in the LN and their recruitment to the lung attenuates bacterial growth. However, their interaction with Mtb-infected macrophages does not promote continued proliferation. We conclude that a lack of sustained expansion by memory-derived T cells in the lung limits the durability of their protection, linking their slower expansion with transient protection in vaccinated mice.

Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection.

Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate the production of Mtb virulence factors, however the mechanisms of this modulation are unknown. To advance our understanding of the mechanisms involved in WhiB3 regulation, we performed Mtb in vitro, intraphagosomal and infected host expression analyses. Our Mtb expression analyses in conjunction with extracellular flux analyses demonstrated that WhiB3 maintains bioenergetic homeostasis in response to available carbon sources found in vivo to establish Mtb infection. Our infected host expression analysis indicated that WhiB3 is involved in regulation of the host cell cycle. Detailed cell-cycle analysis revealed that Mtb infection inhibited the macrophage G1/S transition, and polyketides under WhiB3 control arrested the macrophages in the G0-G1 phase. Notably, infection with the Mtb whiB3 mutant or polyketide mutants had little effect on the macrophage cell cycle and emulated the uninfected cells. This suggests that polyketides regulated by Mtb WhiB3 are responsible for the cell cycle arrest observed in macrophages infected with the wild type Mtb. Thus, our findings demonstrate that Mtb WhiB3 maintains bioenergetic homeostasis to produce polyketide and lipid cyclomodulins that target the host cell cycle. This is a new mechanism whereby Mtb modulates the immune system by altering the host cell cycle to promote long-term persistence. This new knowledge could serve as the foundation for new host-directed therapeutic discovery efforts that target the host cell cycle.

MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBPß regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection.

For efficient clearance of Mycobacterium tuberculosis (Mtb), macrophages tilt towards M1 polarization leading to the activation of transcription factors associated with the production of antibacterial effector molecules such as nitric oxide (NO) and proinflammatory cytokines such as interleukin 1 ß (IL-1ß) and tumor necrosis factor α (TNF-α). At the same time, resolution of inflammation is associated with M2 polarization with increased production of arginase and cytokines such as IL-10. The transcriptional and post-transcriptional mechanisms that govern the balance between M1 and M2 polarization, and bacteria-containing processes such as autophagy and trafficking of Mtb to lysosomes, are incompletely understood. Here we report for the first time, that the transcription factor KLF4 is targeted by microRNA-26a (miR-26a). During Mtb infection, downregulation of miR-26a (observed both ex vivo and in vivo) facilitates upregulation of KLF4 which in turn favors increased arginase and decreased iNOS activity. We further demonstrate that KLF4 prevents trafficking of Mtb to lysosomes. The CREB-C/EBPß signaling axis also favors M2 polarization. Downregulation of miR-26a and upregulation of C/ebpbeta were observed both in infected macrophages as well as in infected mice. Knockdown of C/ebpbeta repressed the expression of selected M2 markers such as Il10 and Irf4 in infected macrophages. The importance of these pathways is substantiated by observations that expression of miR-26a mimic or knockdown of Klf4 or Creb or C/ebpbeta, attenuated the survival of Mtb in macrophages. Taken together, our results attribute crucial roles for the miR-26a/KLF4 and CREB-C/EBPßsignaling pathways in regulating the survival of Mtb in macrophages. These studies expand our understanding of how Mtb hijacks host signaling pathways to survive in macrophages, and open up new exploratory avenues for host-targeted interventions.

Extrapulmonary Tuberculosis: Pathophysiology and Imaging Findings.

Extrapulmonary tuberculosis (TB) represents approximately 15% of all TB infections. It is difficult to diagnose on the basis of imaging characteristics and clinical symptoms, and biopsy is required in many cases. Radiologists must be aware of the imaging findings of extrapulmonary TB to identify the condition in high-risk patients, even in the absence of active pulmonary infection. In extrapulmonary TB, the lymphatic system is most frequently affected. The presence of necrotic lymph nodes and other organ-specific imaging features increases the diagnostic probability of extrapulmonary TB. Disseminated infection and central nervous system involvement are the most frequent manifestations in immunosuppressed patients. Renal disease can occur in immunocompetent patients with very long latency periods between the primary pulmonary infection and genitourinary involvement. In several cases, gastrointestinal, solid-organ, and peritoneal TB show nonspecific imaging findings. Tuberculous spondylitis is the most frequent musculoskeletal manifestation. It is usually diagnosed late and affects multiple vertebral segments with extensive paraspinal abscess. Articular disease is the second most frequent musculoskeletal manifestation, and synovitis is its predominant imaging finding.©RSNA, 2019.

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis.

RATIONALE: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. OBJECTIVES: To identify a functional role of platelets in the innate inflammatory and matrix-degrading response in TB. METHODS: Markers of platelet activation were examined in plasma from 50 patients with TB before treatment and 50 control subjects. Twenty-five patients were followed longitudinally. Platelet-monocyte interactions were studied in a coculture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qRT-PCR, Luminex multiplex arrays, matrix degradation assays, and colony counts. Immunohistochemistry detected CD41 (cluster of differentiation 41) expression in a pulmonary TB murine model, and secreted platelet factors were measured in BAL fluid from 15 patients with TB and matched control subjects. MEASUREMENTS AND MAIN RESULTS: Five of six platelet-associated mediators were upregulated in plasma of patients with TB compared with control subjects, with concentrations returning to baseline by Day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 (matrix metalloproteinase-1) was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion, which drove type I collagen degradation. Platelets increased monocyte IL-1 and IL-10 and decreased IL-12 and MDC (monocyte-derived chemokine; also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model, and secreted platelet mediators were upregulated in human BAL fluid and correlated with MMP and IL-1ß concentrations. CONCLUSIONS: Platelets drive a proinflammatory, tissue-degrading phenotype in TB.

Nutritional status of tuberculosis patients, a comparative cross-sectional study.

BACKGROUND: Each year, more than 13.7 million people became an active case of tuberculosis and more than 1.5 million cases of TB patient will die. The association between TB and malnutrition is bi-directional, TB leads the patient to malnutrition, and malnutrition increases the risk of developing active TB by 6 to 10 times. Improving the nutrition of individual greatly reduces tuberculosis. The aims of this study were to assess the nutritional status and determinants of underweight among TB patients. METHODS: A comparative cross-sectional study design was implemented. The sample size was calculated using 95% CI, 90% power, the prevalence of malnutrition in TB patients 50%, TB patients to TB free resident ratio of 3, the design effect of 2 and a 5% non-response rate. Systematic random sampling was used to select TB patients and simple random sampling technique was used to select TB free residents. The data were collected from July 2015-May 2018. The data were collected by interviewing the patient, measuring anthropometric indicators and collecting the stool and blood samples. The data were entered into the computer using Epi-info software and analyzed using SPSS software. Descriptive statistics were used to find the proportion of malnutrition. Binary logistic regression was used to identify the determinants of malnutrition. RESULTS: A total of 5045 study participants (1681 TB patients and 3364 TB free residents) were included giving for the response rate of 93.1%. The prevalence of underweight among TB patients was 57.17% (95% CI: 54.80, - 59.54%) and 88.52% of TB patients were anemic. The prevalence of malnutrition (underweight) among TB free residents was 23.37% (95% CI: 21.93-24.80). The nutritional status of TB patients was determined by site of infection AOR: 0.68 [0.49-0.94], sex of the patient AOR: 0.39 [0.25-0.56], residence AOR: 3.84 [2.74-5.54], intestinal parasite infection AOR: 7 [5.2-9.95], problematic alcohol use AOR: 1.52 [1.17-2.13]. CONCLUSION: High proportions of TB patients were malnourished. TB patients were highly susceptible to malnutrition and even a very distal reason for malnutrition in the community became a proximal cause for TB patients.

Evaluation of Clinical and Laboratory Characteristics of Children with Pulmonary and Extrapulmonary Tuberculosis.

Background and objective: Tuberculosis (TB) is an important public health problem in both developing and developed countries. Childhood TB is also an important epidemiological indicator in terms of forming the future TB pool. The diagnosis of TB is difficult in children due to the lack of a standard clinical and radiological description. We aimed to evaluate and compare the clinical, laboratory, and radiologic findings of childhood pulmonary and extrapulmonary TB. Material and Methods: The medical records of patients hospitalized with the diagnosis of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) between December 2007 and December 2017 were evaluated retrospectively. Results: There were 163 patients diagnosed with TB with 94 females (57.7%) and 69 males (42.3%). Seventy-three patients (44.8%) had PTB, 71 (43.6%) patients had EPTB, and 19 patients (11.7%) had both PTB and EPTB, called as disseminated TB. Ninety-six (58.9%) patients had tuberculin skin test (TST) positivity and 64 patients (39.3%) had interferon-gamma release assay (IGRA) positivity. Acid-resistant bacteria were observed in 34 (20.9%) body fluid samples and culture positivity was observed in 33 (20.2%) samples. Comparison of PTB, EPTB, and disseminated TB revealed that low socioeconomic status, TB contact, and low body weight were more common in disseminated TB, and TST positivity was more common in PTB. Conclusion: Malnutrition, low socioeconomic status, and TB contact were important diagnostic variables in our study and all three parameters were more common in disseminated TB. Tuberculosis should be considered in patients admitted with different complaints and signs in populations with high TB incidence and low socioeconomic status.

[Characteristics of the macronutrient composition of diet and some somatometric indicators of patients with tuberculosis].

Relevance of the diet to the physiological needs of the organism is an important factor determining the incidence of tuberculosis in the world and effectiveness of its treatment. The need to study actual nutrition and nutritional status is determined by its significant changes in recent decades. Aim: to study the actual nutrition and assess somatometric indicators of the nutritional status of patients with pulmonary tuberculosis in the acute stage. Material and methods. 217 men and 83 women, the average age of 42.9±0.7 years have been examined. Design: cross-sectional (simultaneous) epidemiological study. Research period: 2018. The method of analyzing the frequency of food consumption for the month preceding hospitalization has been applied. The somatometric indicators (height, body weight, waist, hip, shoulder girth) have been analysed, body mass index (BMI) have been determined. Results and discussion. 77.7±2.4% showed non-compliance of the diet energy with the recommended values, an imbalance in diet according to the content of macronutrients was noted in 88.0%, insufficient amount of protein in the diet, taking into account the existing disease, in particular - animal protein was observed in 68.3% of the examined. Excessive intake of fats, including saturated fatty acids took place in 52.0%, cholesterol in 51.0%, as well as insufficient intake of dietary fiber was revealed in 38.7% of the examined. 19.3% had a malnutrition degree 1 (according to BMI), 11.7% had a 2nd degree, and 2% had a 3rd degree, respectively. BMI within normal limits (according to WHO criteria) was recorded in 57.7% of patients. The proportion of patients with overweight and obesity did not exceed 10% (7.3 and 2.0%, respectively). Conclusion. The assessment of the nutritional status of patients suffering from tuberculosis and the identification of the macronutrient imbalance of their diet determine the need for their correction in the organization of therapeutic nutrition.

4-1BB expression on MAIT cells is associated with enhanced IFN-γ production and depends on IL-2.

The role of MAIT cells in immunity against Mycobacterium tuberculosis infection in humans is still largely unexplored. In this study, we investigated the functional role of 4-1BB on MAIT cells. We found that 4-1BB was highly up-regulated on MAIT cells from tuberculous pleural effusions following Mtb antigen stimulation and its level of expression correlated with IFN-γ and IL-17 production. 4-1BB expression on MAIT cells in response to Mtb antigens was partially dependent on IL-2 and was associated with common γ chain receptor. By transcriptome sequencing, we identified numerous differentially expressed genes between 4-1BB- and 4-1BB+ MAIT cells. GO enrichment and KEGG pathway analysis of differentially expressed genes identified enriched pathways that included T-cell receptor and NF-κB signaling pathways. It is concluded that 4-1BB has the potential to be used as a biomarker to identify MAIT cells with enhanced IFN-γ and IL-17 responses that might be associated with tuberculosis infection control.

Stress Hyperglycemia in Patients with Tuberculosis Disease: Epidemiology and Clinical Implications.

PURPOSE OF REVIEW: The intersection of tuberculosis (TB) disease and type 2 diabetes mellitus is severely hindering global efforts to reduce TB burdens. Diabetes increases the risk of developing TB disease and negatively impacts TB treatment outcomes including culture conversion time, mortality risk, and TB relapse. Recent evidence also indicates plausible mechanisms by which TB disease may influence the pathogenesis and incidence of diabetes. We review the epidemiology of stress hyperglycemia in patients with TB and the pathophysiologic responses to TB disease that are related to established mechanisms of stress hyperglycemia. We also consider clinical implications of stress hyperglycemia on TB treatment, and the role of TB disease on risk of diabetes post-TB. RECENT FINDINGS: Among patients with TB disease, the development of stress hyperglycemia may influence the clinical manifestation and treatment response of some patients and can complicate diabetes diagnosis. Research is needed to elucidate the relationship between TB disease and stress hyperglycemia and determine the extent to which stress hyperglycemia impacts TB treatment response. Currently, there is insufficient data to support clinical recommendations for glucose control among patients with TB disease, representing a major barrier for efforts to improve treatment outcomes for patients with TB and diabetes.

Congenital Tuberculosis: A New Concern in the Neonatal Intensive Care Unit.

BACKGROUND: Congenital tuberculosis (TB) is rare in the United States. Recent immigration patterns to the United States have made the diagnosis of congenital TB an important public health issue. PURPOSE: To explore the epidemiology, pathophysiology, diagnostic evaluation, treatment, and prognosis for congenital TB. The implications for exposed healthcare professionals in the neonatal intensive care unit (NICU) setting are also explored. METHODS/SEARCH STRATEGY: Relevant articles were accessed via PubMed, CINAHL, and Google Scholar. FINDINGS/RESULTS: Until 1994, fewer than 400 cases of confirmed congenital TB had been reported in the literature worldwide. An additional 18 cases were reported from 2001 to 2005. Neonatal providers need to be aware of the potential for congenital TB infection as the immigrant population in the United States continues to increase, many of whom originate from TB endemic countries. IMPLICATIONS FOR PRACTICE: The interpretation of TB-specific tests is problematic in newborns due to decreased sensitivity and specificity. Congenital TB should be ruled out in infants with signs and symptoms of sepsis or pneumonia and in whom broad-spectrum antibiotic therapy does not improve their clinical status. IMPLICATIONS FOR RESEARCH: The interpretation of TB-specific tests is problematic in newborns due to decreased sensitivity and specificity; more research is needed regarding best practice in diagnosis. Established protocols are needed to address the healthcare of TB-exposed providers in the NICU.

Tuberculosis and interleukin blocking monoclonal antibodies: Is there risk?

Several new monoclonal antibodies that interfere with interleukin (IL) cascades have come to market in recent years. They follow a generation of drugs that block tumor necrosis factor (TNF). It has been well established that TNF is important in the containment of Mycobacterium tuberculosis (Mtb) and that blocking this cytokine increases the risk of tuberculosis (TB) infection. Thus, judicious screening for Mtb of patients taking TNF blocking drugs has been the standard of care. It remains unclear if the newer monoclonal, interleukin blocking drugs, which affect IL-12, IL-23, and IL-17 pathways are associated with risk of Mtb reactivation. Herein we discuss what is known about the immunologic response to Mtb and discuss the data that is currently available for the new interleukin monoclonal antibody blocking medications regarding the risk of latent TB reactivation or active TB infection.