BCG Vaccine Protection Against Mycobacterium tuberculosis Infection by Level of Exposure in The Gambia.

In Indonesia, BCG vaccine protection against Mycobacterium tuberculosis infection decreased with increasing exposure to the pathogen. We aimed to validate these findings in Africa. Poisson regression was used to estimate BCG protection, stratified by pathogen exposure using an exposure score, against enzyme-linked immunospot assay conversion at 3 months in 220 Gambian case contacts. Although the interaction between BCG and exposure was not significant (P = .13), BCG protection was strongest in the lowest-exposure tertile (relative risk, 0.35 [95% confidence interval, .15-.82; P = .02] vs 0.50 [.30-.83; P = .008] and 0.71 (.45-1.13; P = .1] for the middle and highest-exposure tertiles, respectively. These results are consistent with those from Indonesia.

Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia.

BACKGROUND: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance. METHODS: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point. RESULTS: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04). CONCLUSIONS: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses.

BACKGROUND: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance." METHODS: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. RESULTS: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. CONCLUSIONS: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection.

Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine-induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine-induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B-cell antibody and "trained" innate cells as alternative mediators of protective immunity is explored.

Early clearance of Mycobacterium tuberculosis: a new frontier in prevention.

Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for EC comes from case contact studies that consistently show that a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, natural killer T cells, mucosa-associated invariant T cells and cd T cells may assist. How EC may be impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection.

Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections.

OBJECTIVES: Recently published guidelines on the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend against administering vancomycin by continuous infusion on the basis of insufficient studies comparing this with intermittent infusion. We compared outcomes of patients treated with continuous infusion and intermittent infusion of vancomycin. PATIENTS AND METHODS: Data for outpatients treated with continuous infusion and intermittent infusion of vancomycin were compared utilizing rates of clinical failure defined as the need for unplanned re-admission, change of antibiotics or extension of therapy. RESULTS: A total of 244 patients met the inclusion criteria, with 188 receiving continuous infusion and 56 intermittent infusion of vancomycin. The endpoint occurred in 21.3% and 30.4% of those receiving continuous infusion and intermittent infusion, respectively (relative risk 0.701, 95% CI 0.432-1.136, P = 0.159). Patient characteristics differed slightly between the two groups; however, logistic regression to adjust for differences in age, co-morbidity, subtherapeutic levels and prosthetic devices did not substantially alter this result. CONCLUSIONS: No difference in rates of clinical failure of continuous infusion and intermittent infusion of vancomycin was observed in this outpatient cohort.

Neutrophils and lymphocytes in relation to MMP-8 and MMP-9 levels in pulmonary tuberculosis and HIV co-infection.

Background: Matrix metalloproteinase (MMP) activity has an important role in lung cavitary formation occurred in pulmonary tuberculosis (TB). Low number and viability of CD4 + T-lymphocytes in patients with TB/HIV co-infection leads to impaired neutrophils production, causing further impaired MMPs production. Objective: To explore association of neutrophils and lymphocytes count to MMP-8 and MMP-9 among pulmonary TB patients with cavitary lesion and HIV co-infection. Methods: We conducted a cross-sectional study using a purposive sampling technique among patients with non-cavitary TB (n = 50), cavitary TB (n = 50) and TB/HIV (n = 27). Complete blood count was examined, including neutrophils and lymphocytes count. MMP-8 and MMP-9 were measured from plasma samples using ELISA method. Statistical analysis was conducted to determine the relation between neutrophils, lymphocytes and MMPs. Result: MMP-8 and MMP-9 were positively correlated with neutrophils, but not to lymphocytes in all groups. Neutrophils, lymphocytes, and MMP-9 were significantly lower in TB/HIV co-infection, whereas MMP-8 was higher compared to new pulmonary TB. Interestingly, in cavitary TB, low lymphocytes were significantly correlated with higher level of MMP-8 and larger extent of lung affected. Conclusion: MMP-8 and MMP-9 are associated with neutrophil count, suggesting that neutrophils contribute significantly to their secretion. MMP-8 is significantly higher in TB/HIV co-infection and extent of lung damage in cavitary TB with lower lymphocyte count. This study suggests that lower lymphocyte level is related to higher neutrophil orchestrated inflammation, leading to tissue destruction.

Contact Tracing: A Memory Task With Consequences for Public Health.

In the battle for control of coronavirus disease-19 (COVID-19), we have few weapons. Yet contact tracing is among the most powerful. Contact tracing is the process by which public-health officials identify people, or contacts, who have been exposed to a person infected with a pathogen or another hazard. For all its power, though, contact tracing yields a variable level of success. One reason is that contact tracing's ability to break the chain of transmission is only as effective as the proportion of contacts who are actually traced. In part, this proportion turns on the quality of the information that infected people provide, which makes human memory a crucial part of the efficacy of contact tracing. Yet the fallibilities of memory, and the challenges associated with gathering reliable information from memory, have been grossly underestimated by those charged with gathering it. We review the research on witnesses and investigative interviewing, identifying interrelated challenges that parallel those in contact tracing, as well as approaches for addressing those challenges.

Rothia aeria as a cause of sepsis in a native joint.

Rothia aeria is a recently described Gram-positive rod from the family Micrococcaceae. An elderly woman with rheumatoid arthritis and dental abscesses who was undergoing immunosuppression had R. aeria isolated from synovial fluid. This report characterizes this rare organism and contributes to the literature on its pathogenicity and likely oral source.

High specificity of OraQuick® rapid HIV-1/2 antibody testing during dengue infection.

BACKGROUND: OraQuick® is a rapid test with high specificity demonstrated in non-dengue endemic settings. However, reports of false positive OraQuick® results suggest poor specificity in the context of dengue fever. OBJECTIVES: To assess the specificity of OraQuick® for HIV-1/2 in patients with dengue fever. STUDY DESIGN: In a study performed across two Singapore hospitals, adult participants meeting WHO 2009 criteria for probable dengue (fever >37.5 °C plus two other clinical or haematological criteria) were identified at hospital outpatient clinics from April 2012 to July 2013. Eligible participants were asked for informed consent to complete a questionnaire on HIV risk factors, as well as HIV testing by OraQuick®, fourth-generation EIA and NAAT. Dengue testing was by Dengue Duo NS1Ag + Ab Combo kits. Confirmed dengue was defined as NS1-positive and probable dengue as IgM-positive. RESULTS: Of 152 eligible patients, 82 consented to inclusion in the study. Fifty-two of these had dengue; 43 confirmed and 9 probable cases. All patients with dengue had a negative OraQuick® result, negative EIA and undetectable HIV-1 RNA, corresponding to a specificity of 100 %. CONCLUSIONS: OraQuick® has high specificity in the context of dengue infection. It can be used to diagnose HIV-associated illness as a cause of fever in dengue endemic settings.

Detecting the re-emergent COVID-19 pandemic after elimination: modelling study of combined primary care and hospital surveillance.

AIMS: We aimed to determine the effectiveness of surveillance using testing for SARS-CoV-2 to identify an outbreak arising from a single case of border control failure in a country that has eliminated community transmission of COVID-19: New Zealand. METHODS: A stochastic version of the SEIR model CovidSIM v1.1 designed specifically for COVID-19 was utilised. It was seeded with New Zealand population data and relevant parameters sourced from the New Zealand and international literature. RESULTS: For what we regard as the most plausible scenario with an effective reproduction number of 2.0, the results suggest that 95% of outbreaks from a single imported case would be detected in the period up to day 36 after introduction. At the time point of detection, there would be a median number of five infected cases in the community (95% range: 1-29). To achieve this level of detection, an ongoing programme of 5,580 tests per day (1,120 tests per million people per day) for the New Zealand population would be required. The vast majority of this testing (96%) would be of symptomatic cases in primary care settings and the rest in hospitals. CONCLUSIONS: This model-based analysis suggests that a surveillance system with a very high level of routine testing is probably required to detect an emerging or re-emerging SARS-CoV-2 outbreak within five weeks of a border control failure in a nation that had previously eliminated COVID-19. Nevertheless, there are plausible strategies to enhance testing yield and cost-effectiveness and potential supplementary surveillance systems such as the testing of town/city sewerage systems for the pandemic virus.

Towards elimination of tuberculosis in New Zealand.

New Zealand could be the first country in the world to eliminate tuberculosis (TB). We propose a TB elimination strategy based on the eight-point World Health Organization (WHO) action framework for low incidence countries. Priority actions recommended by the WHO include 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) identify active TB and undertake screening for latent tuberculosis infection (LTBI) in recent TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. In New Zealand, central government needs to take greater responsibility for TB policy and programme governance. Urgent action is required to prevent TB in higher risk groups including Maori communities, and to enable immigration screening to detect and treat LTBI. Clinical services need to be supported to implement new guidelines for LTBI that enable better targeting of screening and shorter, safer treatment regimens. Access to WHO recommended treatment regimens needs to be guaranteed for drug-resistant TB. Better use of existing data could better define priority areas for action and assist in the evaluation of current control activities. Access to GeneXpert® MTB-RIF near the point of care and whole genome sequencing nationally would greatly improve clinical and public health management through early identification of drug resistance and outbreaks. New Zealand already has a world-class TB research community that could be better deployed to assist high-incidence countries through research and training.

IL-32 and its splice variants are associated with protection against Mycobacterium tuberculosis infection and skewing of Th1/Th17 cytokines.

Studies in IL-32 transgenic mice and in vitro suggest that IL-32 may have protective effects against Mycobacterium tuberculosis, but so far there are barely any studies in humans. We studied the role of IL-32 and its splice variants in tuberculosis (TB) in vivo and in vitro. Blood transcriptional analysis showed lower total IL-32 mRNA levels in pulmonary TB patients compared to patients with latent TB infection and healthy controls. Also, among Indonesian household contacts who were heavily exposed to an infectious TB patient, IL-32 mRNA levels were higher among those who remained uninfected compared to those who became infected with M. tuberculosis. In peripheral blood mononuclear cells from healthy donors, we found that IL-32γ, the most potent isoform, was down-regulated upon M. tuberculosis stimulation. This decrease in IL-32γ was mirrored by an increase of another splice variant, IL-32ß. Also, a higher IL-32γ/IL-32ß ratio correlated with IFN-γ production, whereas a lower ratio correlated with production of IL-1Ra, IL-6, and IL-17. These data suggest that IL-32 contributes to protection against M. tuberculosis infection, and that this effect may depend on the relative abundance of different IL-32 isoforms.

High Yield of HIV Testing in Dengue-Like Febrile Illness in Singapore.

Where dengue virus infections are endemic, acute febrile illness is often managed as dengue fever (DF) without diagnostic testing. In a prospective study of 140 patients with clinical features of DF, 3 (2.1%) had acute HIV infection (AHI). We recommend testing for AHI in dengue-like febrile illness.

Latent TB infection and pulmonary TB disease among patients with diabetes mellitus in Bandung, Indonesia.

Background: Screening and treatment of latent TB infection (LTBI) and TB disease could reduce diabetes mellitus (DM)-associated TB. We aimed to describe the prevalence of LTBI and pulmonary TB among patients with DM in a TB-endemic setting. Methods: Patients with DM attending a hospital and community centres in Bandung, Indonesia, underwent LTBI screening using interferon gamma release assay (IGRA). TB was investigated by sputum smear, culture and x-ray. TB contacts from a parallel study were age- and sex-matched to patients with DM to compare LTBI and TB disease prevalence. Results: Of 682 patients with DM screened, 651 (95.5%) were eligible. Among 'TB disease-free' patients, LTBI prevalence was 38.9% (206/530; 95% CI 34.7-43.2). Patients with DM were less likely to be IGRA positive than TB contacts (38.6%, 54/140; 95% CI 30.5-46.6 vs 68.6%, 96/140; 95% CI 60.9-72.3: p<0.001); but had a higher disease prevalence (4.9%, 8/164; 95% CI 1.6-8.2 vs 1.2%, 2/164; 95% CI -0.5 to 2.9: p=0.054). Patients with DM in crowded households had increased risk of LTBI (AOR 1.71; 95% CI 1.19-2.45). Conclusions: LTBI prevalence in patients with DM was lower than in household contacts, but patients with DM were more likely to have TB disease. Further studies should explore possible benefits of LTBI screening and preventive therapy in patients with DM in TB-endemic settings.