Tuberculosis Exposure Research Articles

Use of interferon-gamma release assay and tuberculin skin test in diagnosing tuberculosis in Lithuanian adults: A comparative analysis

Background and objectiveLithuania belongs to the group of countries with a high-incidence of tuberculosis (TB). Some scientific studies show that the interferon-gamma release assay is more accurate and correlates more highly with TB exposure as compared to the tuberculin skin test (TST). This study aimed at comparing the efficacy between the T SPOT TB and TST for diagnosing TB among Lithuanian adults. Materials and methodsIndividuals with diagnosed TB, healthcare workers with known risk for TB and individuals without any known risk for TB underwent clinical examinations, interviews about their history of TB exposure and chest radiography. Then the TST and the T SPOT TB were performed on patients. ResultsA positive T SPOT TB was more common in the group with diagnosed TB compared to healthcare workers and the low risk for TB groups (97.5%, 36.4%, and 0%, respectively, P<0.01). Positive TST results did not differ between the groups with diagnosed TB and the healthcare workers (92.5% vs. 95.5%, P>0.05). Agreement between TST and T SPOT TB was poor (kappa 0.14, P>0.05). T SPOT TB had higher specificity and sensitivity compared to TST (area under the ROC 0.9±0.04, P<0.01, vs. 0.5±0.06, P>0.05). ConclusionsThe T SPOT TB showed greater accuracy in diagnosing TB than TST did. Positive T SPOT TB result but not the TST was more common in patients with diagnosed TB.

A Collaborative Response by Public Health and Local Hospitals to a NICU Tuberculosis Exposure

BackgroundEarly recognition of tuberculosis (TB) cases is critical to prevent spread. Infants are at high risk for TB acquisition after exposure. A TB case went unrecognized despite seeking medical attention in December 2016 for a cough and suspicious radiographic and laboratory testing. During a two week period in November and December 2016 the case visited an infant in a Neonatal Intensive Care Unit (NICU) almost daily for extended periods of time. The NICU was housed in a local community hospital, but staffed by personnel from a separate local children’s hospital. On January 3, 2017, Summit County Public Health was notified of the case and after ascertaining the potential NICU TB exposure began a collaborative contact investigation with the community hospital and the children’s hospital staff, newborns and visitors to the NICU.MethodsThis observational study describes a TB contact investigation of potentially exposed persons in a NICU. The three institutions jointly developed a plan whereby the children’s hospital notified families of the potentially exposed babies, provided prophylactic anti-tubercular medication and follow-up screening. The hospitals’ Infection Preventionists notified and tested the potentially exposed staff. The health department screened the case’s family, personal contacts, and any identified or concerned NICU visitors. At the onset of the investigation the three institutions held a joint press conference. The investigation began in early January 2017 and ended late April 2017.Results TotalInfants potentially exposed68Families contacted68Infants evaluated62Infants put on INH prophylaxis31Infants tested at 10–12 weeks47Infants tested positive0Employees tested183Employees tested positive0 ConclusionAn after-action review revealed strengths, weaknesses and lessons learned. One successful decision was the planned press conference that provided media and public with transparent, consistent messages. A weakness was the inability to identify visitors since there was no NICU visitor log. Therefore visitors other than parents could not be individually contacted about exposure and screening. This investigation successfully involved three different community institutions and was conducted with minimal disruption and public concern.Disclosures All authors: No reported disclosures.

Perceived Barriers to Adherence to Tuberculosis Infection Control Measures among Health Care Workers in the Dominican Republic

INTRODUCTION Health care workers have an increased risk of infection due to occupational Mycobacterium tuberculosis exposure, including multidrug-resistant strains. Health care workers' risk of developing tuberculosis is greater than that of the general population, whether in low-, intermediate- or high-incidence countries. Adherence to infection control measures (administrative controls, environmental controls, and personal respiratory protection) is essential to reduce risk of disease transmission between suspected tuberculosis patients and health care workers, but for different reasons, both objective and subjective, adherence is low. Identifying the causes of low adherence is a prerequisite to effective programming to reduce risk. OBJECTIVE Identify perceived barriers to adherence to tuberculosis infection control measures among health care workers in the Dominican Republic. METHODS During August 2014, a qualitative study was conducted in two tertiary-level hospitals in different regions of the Dominican Republic. A semi-structured interview guide of nine questions was developed, based on the scientific literature and with consensus of clinical experts. Nine semi-structured interviews were conducted with a purposive sample of seven physicians (five men, two women) and two baccalaureate nurses (both women) working in the emergency medicine, internal medicine or nursing departments of those institutions. Question topics included clinical experience of M. tuberculosis infection and disease; knowledge of disease transmission and preventive practices; clinical management strategies; and perceptions of effectiveness of directly observed treatment, short-course, and disease coping strategies. RESULTS Perceived barriers were described as: 1) sense of invincibility of health care workers; 2) personal beliefs of health care workers related to direct patient communication; 3) low provider-to-patient ratios in hospitals; 4) absence of tuberculosis isolation units for patients within hospitals; and 5) limited availability of protective masks for health care workers. CONCLUSIONS Our results highlight that perceived barriers at the individual or institutional level may hinder how health care workers understand and comply with preventive strategies to reduce risk of tuberculosis transmission. Addressing these barriers by strengthening infection control program infrastructure and implementing educational interventions within institutions may reduce risk of nosocomial tuberculosis transmission to health care workers. KEYWORDS Health care providers, infection control, infectious disease transmission, health care associated infection, nosocomial infection, Mycobacterium tuberculosis occupational exposure, occupational health, qualitative research, tuberculosis, Dominican Republic.

Perceived Barriers to Adherence to Tuberculosis Infection Control Measures among Health Care Workers in the Dominican Republic

INTRODUCTION Health care workers have an increased risk of infection due to occupational Mycobacterium tuberculosis exposure, including multidrug-resistant strains. Health care workers' risk of developing tuberculosis is greater than that of the general population, whether in low-, intermediate- or high-incidence countries. Adherence to infection control measures (administrative controls, environmental controls, and personal respiratory protection) is essential to reduce risk of disease transmission between suspected tuberculosis patients and health care workers, but for different reasons, both objective and subjective, adherence is low. Identifying the causes of low adherence is a prerequisite to effective programming to reduce risk. OBJECTIVE Identify perceived barriers to adherence to tuberculosis infection control measures among health care workers in the Dominican Republic. METHODS During August 2014, a qualitative study was conducted in two tertiary-level hospitals in different regions of the Dominican Republic. A semi-structured interview guide of nine questions was developed, based on the scientific literature and with consensus of clinical experts. Nine semi-structured interviews were conducted with a purposive sample of seven physicians (five men, two women) and two baccalaureate nurses (both women) working in the emergency medicine, internal medicine or nursing departments of those institutions. Question topics included clinical experience of M. tuberculosis infection and disease; knowledge of disease transmission and preventive practices; clinical management strategies; and perceptions of effectiveness of directly observed treatment, short-course, and disease coping strategies. RESULTS Perceived barriers were described as: 1) sense of invincibility of health care workers; 2) personal beliefs of health care workers related to direct patient communication; 3) low provider-to-patient ratios in hospitals; 4) absence of tuberculosis isolation units for patients within hospitals; and 5) limited availability of protective masks for health care workers. CONCLUSIONS Our results highlight that perceived barriers at the individual or institutional level may hinder how health care workers understand and comply with preventive strategies to reduce risk of tuberculosis transmission. Addressing these barriers by strengthening infection control program infrastructure and implementing educational interventions within institutions may reduce risk of nosocomial tuberculosis transmission to health care workers. KEYWORDS Health care providers, infection control, infectious disease transmission, health care associated infection, nosocomial infection, Mycobacterium tuberculosis occupational exposure, occupational health, qualitative research, tuberculosis, Dominican Republic.

Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis.

Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T-cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV-infected and -uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV-exposed, -infected and -uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric- and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV-exposed uninfected (HEU) and M.tb-infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV-infected (HI) children were similar to unexposed uninfected controls; however, HAART-mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine-pyrrole-2,3-dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase-1. Increased MDSC were paralleled by reduced plasma IP-10 and thrombospondin-2 levels in HEU and significantly increased plasma IL-6 in HI HHC. Current investigations into MDSC-targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40–CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.

Tuberculosis exposure, infection and disease in children: a systematic diagnostic approach.

The accurate diagnosis of tuberculosis (TB) in children remains challenging. A myriad of common childhood diseases can present with similar symptoms and signs, and differentiating between exposure and infection, as well as infection and disease can be problematic. The paucibacillary nature of childhood TB complicates bacteriological confirmation and specimen collection is difficult. In most instances intrathoracic TB remains a clinical diagnosis. TB infection and disease represent a dynamic continuum from TB exposure with/without infection, to subclinical/incipient disease, to non-severe and severe disease. The clinical spectrum of intrathoracic TB in children is broad, and the classification of clinical, radiological, endoscopic, and laboratory findings into recognized clinical syndromes allows a more refined diagnostic approach in order to minimize both under- and over-diagnosis. Bacteriological confirmation can be improved significantly by collecting multiple, high-quality specimens from the most appropriate source. Mycobacterial testing should include traditional smear microscopy and culture, as well as nucleic acid amplification testing. A systematic approach to the child with recent exposure to TB, or with clinical and radiological findings compatible with this diagnosis, should allow pragmatic classification as TB exposure, infection, or disease to facilitate timely and appropriate management. It is important to also assess risk factors for TB disease progression and to undertake follow-up evaluations to monitor treatment response and ongoing evidence supporting a TB, or alternative, diagnosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s41479-016-0023-9) contains supplementary material, which is available to authorized users.

Performance of a lateral flow immunochromatography test for the rapid diagnosis of active tuberculosis in a large multicentre study in areas with different clinical settings and tuberculosis exposure levels.

Tuberculosis (TB) continues to cause an outsized burden of morbidity and mortality worldwide, still missing efficient and largely accessible diagnostic tools determining an appropriate control of the disease. Serological tests have the potentially to impact TB diagnosis, in particular in extreme clinical settings. The diagnostic performances of the TB-XT HEMA EXPRESS (HEMA-EXPRESS) immunochromatographic rapid test for active TB diagnosis, based on use of multiple Mycobacterium tuberculosis (MTB) specific antigens, have been evaluated in a large study multicentre TB case-finding study, in populations with different exposure level to TB. A total of 1,386 subjects were enrolled in the six participating centres in Peru: 290 active-TB and 1,096 unaffected subjects. The TB prevalence (overall 20.5%) varied between 4.0% and 41.1% in the different study groups. Overall, the HEMA-EXPRESS test had 30.6% sensitivity (range 3.9-77.9%) and 84.6% specificity (range 51.6-97.3%). A significant inverse correlation between test accuracy (overall 73.5%, range 40.4-96.4%) and TB prevalence in the various study populations was observed (Pearson's r=-0.7985; P=0.05). HEMA-EXPRESS, is rapid and relatively inexpensive test suitable for routine use in TB diagnosis. In low TB prevalence conditions, test performance appears in line with WHO Target Product Profile for TB diagnostics. Performances appear suboptimal in high TB prevalence settings. Appropriate set-up in operative clinical settings has to be considered for novel serological tests for TB diagnosis, particularly for formats suitable for point-of-care use.

Evaluation of Tuberculin Skin Test (TST) in Medical Students in Mazandaran University of Medical Sciences, Sari, Iran

&lt;p&gt;&lt;strong&gt;BACKGROUND: &lt;/strong&gt;Working in health care units has been known as occupational risk factor in mycobacterium tuberculosis (TB) infection. The TB exposure rate in medical students is more than other people. In several studies significant correlation has been reported between hospital presence hours and positive PPD test prevalence. With regard to morbidity of several medical students and nursing staff due to primary tuberculosis in recent years, we decided to investigate positive tuberculin skin test (TST) prevalence in medical students and examine correlation between positive cases prevalence with presence hours in hospitals.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;METHODS: &lt;/strong&gt;This was a cross sectional study and 297 medical students of Mazandaran University of medical sciences were investigated. TST was done with Mantoux method. After 48 hours, injection site induration was measured. Subjects that had induration &amp;lt;10 millimeters were injected again (1-3 weeks later) with same method. (As a booster dose)&lt;/p&gt;&lt;p&gt;&lt;strong&gt;RESULTS: &lt;/strong&gt;32 cases (10.7%) had positive test at the first phase. Second phase was done on rest 265 persons and 20 cases had positive test. In summation 52 positive cases (17.5%) were observed. 21 cases of 151 persons (13.9%) in group with &amp;lt;100 hours/annual hospital presence, had positive tests. 21 cases of 71 persons (16.9%) in group with 100-1000 h/a hospital presence (Extern) and 19 cases of 75 people (25.3%) those who had &amp;gt;1000 h/a hospital presence(Intern), had positive tests. There was a meaningful statically difference in positive tests, between groups &amp;lt; 1000 hours exposure and the other who had &amp;gt; 1000 hours contact (p=0.032).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;CONCLUSIONS: &lt;/strong&gt;Because of, Interns’ high responsibilities and their more involvement in patient’s diagnostic and therapeutic process, they have high chance to contact with undiagnosed and diagnosed tuberculosis patients. Due to these reasons, TB infection rate is increasing among Interns. As a result of these findings, performing PPD test should be considered at the beginning of entrance to hospital departments and then annually. Necessary tasks and following up are needed to new positive cases.&lt;/p&gt;

Screening for tuberculosis in neuro-ophthalmology

ABSTRACTIntroduction: Timely detection of Mycobacterium tuberculosis (Mtb) remain critical in the effective management of patients with suspected tuberculosis (TB) disease. While recommendations for determination of latent TB or TB exposure in industrialized countries support the use of interferon-gamma release assays (IGRA), including the QuantiFERON Gold In-Tube (QFT-GIT) and T-SPOT.TB tests, disagreement exists within neuro-ophthalmologic practice on screening protocols for TB which affects ocular function.Areas covered: The authors have reviewed the current literature discussing the manifestation of tuberculosis in neuro-ophthalmic disease. Our literature search expands on current recommendations for TB screening in neuro-ophthalmology, including a comparison of the currently available tests for screening: the TST, QFT-GIT, and T-SPOT.TB tests. We review the literature on regional TB prevalence as it applies to clinical decision making for screening, as well as medical and social factors which may create a high-risk individual for neuro-ophthalmic tuberculosis.Expert commentary: The authors recommend that protocols for screening for neuro-ophthalmic tuberculosis involve directing recently developed IGRAs towards patients considered at high risk as determined by patient history, including medical and social risk factors, as well as epidemiologic data for TB prevalence in the region under consideration.

Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis.

Accumulating evidence from experimental animal models suggests that antibodies play a protective role against tuberculosis (TB). However, little is known about the antibodies generated upon Mycobacterium tuberculosis (MTB) exposure in humans. Here, we performed a molecular and functional characterization of the human B‐cell response to MTB by generating recombinant monoclonal antibodies from single isolated B cells of untreated adult patients with acute pulmonary TB and from MTB‐exposed healthcare workers. The data suggest that the acute plasmablast response to MTB originates from reactivated memory B cells and indicates a mucosal origin. Through functional analyses, we identified MTB inhibitory antibodies against mycobacterial antigens including virulence factors that play important roles in host cell infection. The inhibitory activity of anti‐MTB antibodies was directly linked to their isotype. Monoclonal as well as purified serum IgA antibodies showed MTB blocking activity independently of Fc alpha receptor expression, whereas IgG antibodies promoted the host cell infection. Together, the data provide molecular insights into the human antibody response to MTB and may thereby facilitate the design of protective vaccination strategies.

Rhinosinusitis and Parotid Enlargement in a Young African American Man

AyoungAfricanAmericanmanpresentedwith a6-monthhistoryof nasal congestion, facial pressure, purulent rhinorrhea, and hypo-osmia that had not improved despite multiple coursesofantibiotics andsteroids.Hismedical historywassignificant for chronic rhinosinusitis, allergic rhinitis, andasthma, forwhichhetookfluticasonepropionateandsalmeterol (Advair) and albuterol. A review of systems revealed epiphora and ocular crusting for 4 months. Findings on nasal endoscopy includedbilateral turbinate hypertrophy and significant nasal crusting.A computed tomographic (CT) scanof the sinuses revealeddiffusemucosal thickening consistent with pansinusitis (Figure, A). All laboratory results from an autoimmune workup were normal for angiotensin-converting enzyme (ACE) level, antineutrophil cytoplasmic antibodies, antinuclear antibody, and immunoglobulin levels. He had a normal chest radiograph. The patient was lost to follow-up but returned several months later with 6weeks of progressive bilateral parotid swelling (Figure, B). His parotid glands were diffusely enlarged and tender, and his facial function was normal. Radiologically, nomasses or sialoliths were seen (Figure, C). His only associated symptomswere fevers and fatigue. A history of recent tuberculosis exposure was obtained. Test results for SSa/SSb levels, human immunodeficiency virus (HIV), polymerase chain reaction (PCR), mumps titers, rapid plasma reagin, amylase, cytomegalovirus PCR, and quantiferon testing were negative. A superficial parotid biopsy revealed noncaseating granulomatous inflammation (Figure, D). Parotid biopsy specimen D Axial postcontrast CT of neck C Preoperative photograph B Coronal noncontrast CT image A

Negative Screening Does Not Rule Out the Risk of Tuberculosis in Patients with Inflammatory Bowel Disease Undergoing Anti-TNF Treatment: A Descriptive Study on the GETAID Cohort.

to describe the characteristics of incident cases of tuberculosis [TB] despite negative TB screening tests, in patients with inflammatory bowel disease [IBD] undergoing anti-TNF treatment, and to identify the risk factors involved. A retrospective descriptive study was conducted at GETAID centers on all IBD patients undergoing anti-TNF treatment who developed TB even though their initial screening test results were negative. The following data were collected using a standardized anonymous questionnaire: IBD, and TB characteristics and evolution, initial screening methods and results, and time before anti-TNF treatment was restarted. A total of 44 IBD patients [including 23 men; median age 37 years] were identified at 20 French and Swiss centers at which TB screening was performed [before starting anti-TNF treatment] based on Tuberculin Skin Tests [n = 25], Interferon Gamma Release Assays [n = 12], or both [n = 7]. The median interval from the start of anti-TNF treatment to TB diagnosis was 14.5 months (interquartile range [IQR] 25-75: 4.9-43.3). Pulmonary TB involvement was observed in 25 [57%] patients, and 40 [91%] had at least one extrapulmonary location. One TB patient died as the result of cardiac tamponade. Mycobacterium tuberculosis exposure was thought to be a possible cause of TB in 14 cases [32%]: 7 patients [including 6 health care workers] were exposed to occupational risks, and 7 had travelled to endemic countries. Biotherapy was restarted on 27 patients after a median period of 11.2 months [IQR 25-75: 4.4-15.2] after TB diagnosis without any recurrence of the infection. Tuberculosis can occur in IBD patients undergoing anti-TNF treatment, even if their initial screening results were negative. In the present population, TB was mostly extrapulmonary and disseminated. TB screening tests should be repeated on people exposed to occupational risks and/or travelers to endemic countries. Restarting anti-TNF treatment seems to be safe.

First evaluation of QuantiFERON-TB Gold Plus performance in contact screening.

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2-TB1) was used as an estimate of CD8+ stimulation provided by the TB2. TB2-TB1 values >0.6 IU·mL-1 were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8+ response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection.

Coccidioidal Thyroiditis

Case presentation: A 62-year-old Asian female presented for fine needle aspiration (FNA) of a thyroid nodule. She reported a 1-month history of fever, night sweats, anorexia, odynophagia, and dry cough, accompanied by a 6-kg weight loss. She had recently moved to a neighborhood in southern California with extensive new construction and an arid climate; she denied any sick contacts, recent overseas travel, or known tuberculosis exposure. Her medical history was notable for pulmonary and thyroid nodules discovered at an outside facility. Physical examination was notable for tachycardia and a tender thyroid nodule. Laboratory studies demonstrated mild normocytic anemia, thyroid-stimulating hormone 1.77 mIU/mL (0.27–4.20), and free thyroxine 1.27 ng/dL (0.89–1.76). FNA showed abundant thick colloid and granulomata in a background of mixed inflammation (Fig. 1). Bedside thyroid ultrasound (US) revealed a 3-cm left-sided nodule with minimal hypervascularity and no microcalcification (Fig. 2 A). Computed tomography of the chest showed interval progression in both size and number of clustered lung nodules in the left upper lobe (Fig. 2 B). What is the diagnosis? Fig. 2 View Large Image Figure Viewer

Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages.

Cellular reactive oxygen species (ROS) is a major antibacterial defense mechanism used by macrophages upon activation. Exposure of Mycobacterium tuberculosis (Mtb)-infected macrophages to hypoxia is known to compromise the survival of the pathogen. Here we report that the hypoxia-induced control of intracellular Mtb load in RAW 264.7 macrophages was mediated by regulating the cellular ROS levels. We show that similar to classical activation, hypoxia incubation of macrophages resulted in decreased mitochondrial outer membrane potential (MOMP) and a concomitant increase in the cellular ROS levels. Mitochondrial depolarization and consequently higher ROS could be blocked by knocking down Akt using siRNAs, which acted by inhibiting the switch to glycolytic mode of metabolism, an essential adaptive response upon classical activation or hypoxic incubation of macrophages. Moreover, in the classically activated macrophages or in the macrophages under hypoxia incubation, supplementation with additional glucose had similar effects as Akt knockdown. Interestingly, in both the cases, the reversal of phenotype was linked with the ability of the mitochondrial F0–F1 ATP synthase activity to maintain the MOMP in the absence of oxidative phosphorylation. Both Akt knockdown and glucose supplementation were also able to rescue Mtb survival in these macrophages upon classical activation or hypoxia incubation. These results provide a framework for better understanding of how the interplay between oxygen supply, which is limiting in the human tubercular granulomas, and nutrient availability could together direct the outcome of infections in vivo.

Interferon Gamma Release Assay versus Tuberculin Skin Testing among Healthcare Workers of Highly Diverse Origin in a Moderate Tuberculosis Burden Country.

Health care workers (HCW’s) are always at an increased risk of contracting tuberculosis (TB) infection. In Saudi Arabia, Interferon Gamma Release Assay (IGRA) has not been evaluated as a screening tool for latent TB infection (LTBI) among HCW’s considering their high demographic diversity. During February 2012 to January 2015 a cross sectional study has been conducted in a tertiary care center with maximum demographically diverse staff population in the capital city-Riyadh. After a short interview and consenting, all the candidates were subjected to tuberculin skin test (TST) and QuantiFERON TB gold In-tube test (QFT). A logistic regression analysis was carried out for establishing the associations between putative risk factors and the diagnostic tests. The candidates were classified according to geographical origin and a detailed analysis was conducted on the impact of their origin towards the results of TST and QFT. Of the 1595 candidates enrolled, 90.6% were BCG vaccinated, female (67.9%) and mainly nurses (53.2%). Candidates with high risk of suspected or confirmed TB patient exposure were 56.1% and 76.5% of them had <10 year’s work experience. TST positivity was observed in 503 (31.5%) candidates, while QFT was positive among 399 (25%). Majority of the candidates were non-Saudi (83%) and predominantly (52.4%) from Western Pacific region. Concordant results were obtained in 14.2% of positive cases and 57.7% negative cases. The disagreements between the two tests were relatively high (kappa co-efficient-0.312±0.026, p value- <0.00001) as TST positive/QFT negative discordance was 54.8% while TST negative/QFT positive discordance was 15.7%. Age of the candidates, BCG vaccination, and South East Asian origin were associated with TST positivity while Occupational TB exposure and geographical origin of the candidates were associated with QFT positivity. A regular follow up on recently TST converted candidates showed no progression to active TB. The putative factors associated with the discordance were origin of the candidate (p value <0.001), profession (p value-0.001), BCG vaccination (p value-0.001) and occupational TB exposure level (P value-0.001). The study demonstrated high level prevalence of LTBI among the demographically diverse study candidates. The agreement between QFT and TST was poor, thus QFT alone cannot be recommended in our setting for a routine LTBI screening. Origin of the candidates has strong association with the results of TST and QFT. The discordant results particularly TST negative and QFT positive needs more detailed analysis.

Exposed, but Not Protected: More Is Needed to Prevent Drug-Resistant Tuberculosis in Healthcare Workers and Students.

"Occupational MDR-TB" … "XDR-TB" … "Treatment-induced hearing loss": 3 life-changing messages imparted over the phone. Three personal accounts are shared highlighting the false belief held by many healthcare workers (HCWs) and students in low-resource settings-that they are immune to tuberculosis despite high levels of occupational tuberculosis exposure. This misconception reflects a lack of awareness of tuberculosis transmission and disease risk, compounded by the absence of accurate occupational tuberculosis estimates. As the global problem of drug-resistant (DR) tuberculosis evolves, HCWs are increasingly infected and suffer considerable morbidity and mortality from occupational DR tuberculosis disease. Similarly, healthcare students are emerging as a vulnerable and unprotected group. There is an urgent need for improved detection, vaccines, preventive therapy, treatment, and support for affected HCWs and those they care for, as well as destigmatization of all forms of tuberculosis. Finally, efforts to protect HCWs and prevent DR tuberculosis transmission by universal implementation of tuberculosis infection control measures should be prioritized.

Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands.

In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15-20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies. Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL. Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values. Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.

The occupational risk of tuberculosis in a low-prevalence population.

The incidence of tuberculosis (TB) infection in low-prevalence countries has been declining. Estimates of the risk of occupational TB in these countries are contradictory. To evaluate the risk of occupational TB in a low-prevalence population using a comprehensive database. All compensation claims in British Columbia (BC), Canada, reporting workplace TB exposure for the years 1999-2008 were reviewed. Cases with TB infection were identified for all occupational groups with five or more claims in the decade and analysis provided estimates of incidence rates of active TB and relative risks of latent TB (LTB) infections. There were 70 occupational groups making 639 claims including 100 with LTB and eight with active TB. Only 18 occupations had five or more claims. Four occupational groups had a significantly increased relative risk of infection compared with all other occupational groups. These were employment counsellors, registered nurses, x-ray technicians and home support workers. Active TB infections were relatively rare compared with the general population (1-4 compared with 7-10/100000 person-years, respectively). Few occupational groups were at risk of TB exposure at work on a regular basis. Only a handful had an apparent increased risk of contracting TB and these should be the focus of prevention efforts. Work-related active TB infections are rare hence the burden of occupational TB disease is low in BC.