Treatment Of Latent Infection Research Articles

Efficacy and safety of a preventive strategy against tuberculosis in liver transplantation recipients including the treatment of latent infection with moxifloxacin.

Preventive management of tuberculosis in liver transplantation (LT) is challenging due to difficulties in detecting and treating latent tuberculosis infection (LTBI). The aim of this study was to analyze the safety and efficacy of a screening strategy for LTBI with the inclusion of moxifloxacin as treatment. We performed a retrospective single-center study of all LTs performed between 2016 and 2019 with a minimum 4-year follow-up and a standardized protocol for the evaluation of LTBI. Pretransplant LTBI screening was performed in 191/218 (87.6%) patients, and LTBI was diagnosed in 27.2% of them. Treatment for LTBI was administered to 71.2% of the patients and included moxifloxacin in 75.6% of the cases. After a median follow-up of 1628 days, no cases of active tuberculosis occurred among moxifloxacin-treated patients. The incidence of Clostridioides difficile (0.46vs. 0.38 episodes/1000 transplant-days; p = .8) and multidrug-resistant gram-negative bacilli infection (0vs. 0.7 episodes per 1000 transplant-days; p = .08) were not significantly higher in comparison to patients who did not receive moxifloxacin. A preventive strategy based on systematic LTBI screening and moxifloxacin treatment before LT in positive cases appears safe and effective in preventing the development of tuberculosis in LT recipients. However, our findings are limited by a small sample size; thus, larger studies are required to validate our observations.

Transplantation and immigration: Comparing infectious complications and outcomes between foreign-born and US-born kidney transplant recipients in Minnesota.

Foreign-born kidney transplant recipients (FBKTRs) are at increased risk for reactivation of latent infections that may impact outcomes. We aimed to compare the etiology of infections and outcomes between FBKTR and United States KTRs (USKTR). We performed a retrospective study of patients who underwent kidney transplantation between January 1, 2014 and December 31, 2018 at two transplant centers in Minnesota. Frequency and etiology of infections as well as outcomes (graft function, rejection, and patient survival) at 1-year post-transplant between FBKTR and USKTR were compared. Of the 573 transplant recipients, 124 (21.6%) were foreign-born and 449 (78.4%) US-born. At least one infection occurred in 411 (71.7%) patients (38.2% bacterial, 55% viral, 9.4% fungal). Viral infections were more frequent in FBKTR, particularly BK viremia (38.7%vs. 21.2%, p < .001). No statistical differences were found for bacterial or fungal infections; no parasitic infections were identified in either group. No geographically-restricted infections were noted aside from a single case of Madura foot in a FBKTR. Rejection episodes were more common in USKTR (p = .037), but stable/improving graft function (p = .976) and mortality (p = .451) at 1-year posttransplantation were similar in both groups. After adjusting for covariates, previous transplantation was associated with a higher number of infections (IRR 1.35, 95% confidence intervals 1.05-1.73, p = .020). Although viral infections were more frequent in FBKTR, overall frequency and etiology of most infections and outcomes were similar between FBKTR and USKTR suggesting that comprehensive transplant care is providing timely prevention, diagnosis, and treatment of latent infections in FBKTR.

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria.

One-third of the world's population is estimated to be latently infected with Mycobacterium tuberculosis. This reservoir of bacteria is largely resistant to antimicrobial treatment that often only targets actively replicating mycobacteria, with current treatment for latent infection revolving around inhibiting the resuscitation event rather than preventing or treating latent infection. As a result, antimicrobials that target latent infection often have little to no activity in vivo. Here we report a method of in vitro analysis of physiologically relevant non-replicating persistence (NRP) utilizing cholesterol as the sole carbon source, alongside hypoxia as a driver of Mycobacterium bovis BCG into the NRP state. Using the minimal cholesterol media NRP assay, we observed an increased state of in vitro resistance to front-line anti-tubercular compounds. However, following a phenotypic screen of an approved-drug library, we identified dapsone as a bactericidal active molecule against cholesterol-dependent NRP M. bovis BCG. Through an overexpression trial of probable antimicrobial target enzymes, we further identified FolP2, a non-functional dihydropteroate synthase homologue, as the likely target of dapsone under cholesterol-NRP due to a significant increase in bacterial resistance when overexpressed. These results highlight the possible reason for little in vivo activity seen for current front-line anti-NRP drugs, and we introduce a new methodology for future drug screening as well as a potential role for dapsone inclusion within the current treatment regime.

Potential Impact of Long-Acting Products on the Control of Tuberculosis: Preclinical Advancements and Translational Tools in Preventive Treatment.

A key component of global tuberculosis (TB) control is the treatment of latent TB infection. The use of long-acting technologies to administer TB preventive treatment has the potential to significantly improve the delivery and impact of this important public health intervention. For example, an ideal long-acting treatment could consist of a single dose that could be administered in the clinic (ie, a "1-shot cure" for latent TB). Interest in long-acting formulations for TB preventive therapy has gained considerable traction in recent years. This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of TB drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies.

Mechanism and management of antibiotic drug resistance tuberculosis

Drug resistance in tuberculosis has been shown to result from spontaneous mutation in several chromosomal genes of M.Tuberculosis. Mutation may reduce the medications' capacity to bind to the target genes. In many patients polydrug resistance, multidrug resistance, rifampicin resistance (RR) and extensive drug resistance (XDR) were seen. The diagnosis of drug-resistant TB in HIV-positive persons is more difficult and may be confused with other pulmonary or systemic infections. Management of patients with mono- or poly-resistant TB will be done with standard first line chemotherapy. Treatment of latent infection for people suffering from multidrug resistant bacilli is problematic because the only cure by isoniazid and rifampicin. In the recent cases of severe hepatotoxicity associated with preventive treatment comprising either pyrazinamide and rifampicin or pyrazinamide and fluoroquinolone. The use of dilatory fluoroquinolones, such as moxifloxacin, remarkable improved treatment outcomes of XDR-TB.

Blood transcriptomic biomarkers for tuberculosis screening: time to redefine our target populations?

Blood transcriptomic biomarkers for tuberculosis screening: time to redefine our target populations?

1389. Risk Factors and Clinical Outcomes of Tuberculosis Among Kidney Transplant Recipients in High Endemic Country: A Case–Control Study

BackgroundTuberculosis (TB) is considered as a challenging issue in solid-organ transplant recipients because of high morbidity and mortality. Active TB after transplant can occur from reactivation of latent infection or newly acquired from community. Understanding risk factors and clinical information of TB may provide an appropriate prevention and treatment strategies in this specific patient population; however, most of data were from non-endemic countries.MethodsA single-center, matched case–control study was conducted in our institute. Cases were defined as newly diagnosed proven or probable active TB in patients who underwent kidney transplant between April 1992 and October 2018. For each case, 5 controls were matched by age and sex. Risk factor associated with TB was determined using univariate and multivariate conditional logistic regression.ResultsBetween study period, kidney transplant was performed in 787 patients. None of the recipients was screened or treated for latent tuberculosis. Twenty-seven patients (3.43%) were diagnosed with active TB including 20 proven and 7 probable cases. The overall incidence of TB in our population was 315 cases per 100,000 patients per year. Allograft rejection was significantly associated with active TB (P < 0.001). The median onset of infection was 17 months (IQR, 4–59 months) after transplantation and 3.4 months (IQR, 2.7–16.3 months) after episode of allograft rejection. Majority of patients (96.3%) were cured after complete treatment; however, those with TB remained having significant unfavorable outcomes including higher all-cause mortality and graft loss.ConclusionIncidence of TB in kidney transplant recipients is higher than normal population. Increasing risk of active TB after allograft rejection is probably due to mycobacterial reactivation following high-dose immunosuppression. Since TB is associated with poor post-transplant outcomes, screening, and treatment of latent infection may be beneficial even in endemic country. Disclosures All authors: No reported disclosures.

Treatment of latent infection to achieve tuberculosis elimination in low-incidence countries.

In a Perspective for the Tuberculosis Special Issue, Kevin Schwartzman and colleagues discuss the choices and implications for personal versus public health benefits when pursuing tuberculosis elimination in low-incidence countries.

Safety and Side Effects of Rifampin versus Isoniazid in Children

BackgroundThe treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment — 9 months of isoniazid — has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid.MethodsIn this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis.ResultsOf the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, −0.37 cases per 100 person-years; 95% CI, −0.88 to 0.14).ConclusionsAmong children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209.)

Benzoylphenyl thiocyanates are new, effective inhibitors of the mycobacterial resuscitation promoting factor B protein

BackgroundResuscitation promoting factors (Rpfs) are the proteins involved in the process of reactivation of the dormant cells of mycobacteria. Recently a new class of nitrophenylthiocyanates (NPTs), capable of inhibiting the biological and enzymatic activities of Rpfs has been discovered. In the current study the inhibitory properties of the compounds containing both nitro and thiocyanate groups alongside with the compounds with the modified number and different spatial location of the substituents are compared.MethodsNew benzoylphenyl thiocyanates alongside with nitrophenylthiocyanates were tested in the enzymatic assay of bacterial peptidoglycan hydrolysis as well as against strains of several actinobacteria (Mycobacterium smegmatis, Mycobacterium tuberculosis) on in-lab developed models of resuscitation of the dormant forms.ResultsIntroduction of the additional nitro and thiocyanate groups to the benzophenone scaffold did not influence the inhibitory activity of the compounds. Removal of the nitro groups analogously did not impair the functional properties of the molecules. Among the tested compounds two molecules without nitro group: 3-benzoylphenyl thiocyanate and 4-benzoylphenyl thiocyanate demonstrated the maximum activity in both enzymatic assay (inhibition of the Rpf-mediated peptidoglycan hydrolysis) and in the resuscitation assay of the dormant M. tuberculosis cells.ConclusionsThe current study demonstrates dispensability of the nitro group in the NPT’s structure for inhibition of the enzymatic and biological activities of the Rpf protein molecules. These findings provide new prospects in anti-TB drug discovery especially in finding of molecular scaffolds effective for the latent infection treatment.

Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland

SummaryBackgroundTuberculosis elimination in countries with a low incidence of the disease necessitates multiple interventions, including innovations in migrant screening. We examined a cohort of migrants screened for tuberculosis before entry to England, Wales, and Northern Ireland and tracked the development of disease in this group after arrival.MethodsAs part of a pilot pre-entry screening programme for tuberculosis in 15 countries with a high incidence of the disease, the International Organization for Migration screened all applicants for UK visas aged 11 years or older who intended to stay for more than 6 months. Applicants underwent a chest radiograph, and any with results suggestive of tuberculosis underwent sputum testing and culture testing (when available). We tracked the development of tuberculosis in those who tested negative for the disease and subsequently migrated to England, Wales, and Northern Ireland with the Enhanced Tuberculosis Surveillance system. Primary outcomes were cases of all forms of tuberculosis (including clinically diagnosed cases), and bacteriologically confirmed pulmonary tuberculosis.FindingsOur study cohort was 519 955 migrants who were screened for tuberculosis before entry to the UK between Jan 1, 2006, and Dec 31, 2012. Cases notified on the Enhanced Tuberculosis Surveillance system between Jan 1, 2006, and Dec 31, 2013, were included. 1873 incident cases of all forms of tuberculosis were identified, and, on the basis of data for England, Wales, and Northern Ireland, the estimated incidence of all forms of tuberculosis in migrants screened before entry was 147 per 100 000 person-years (95% CI 140–154). The estimated incidence of bacteriologically confirmed pulmonary tuberculosis in migrants screened before entry was 49 per 100 000 person-years (95% CI 45–53). Migrants whose chest radiographs were compatible with active tuberculosis but with negative pre-entry microbiological results were at increased risk of tuberculosis compared with those with no radiographic abnormalities (incidence rate ratio 3·2, 95% CI 2·8–3·7; p<0·0001). Incidence of tuberculosis after migration increased significantly with increasing WHO-estimated prevalence of tuberculosis in migrants' countries of origin. 35 of 318 983 pre-entry screened migrants included in a secondary analysis with typing data were assumed index cases. Estimates of the rate of assumed reactivation tuberculosis ranged from 46 (95% CI 42–52) to 91 (82–102) per 100 000 population.InterpretationMigrants from countries with a high incidence of tuberculosis screened before being granted entry to low-incidence countries pose a negligible risk of onward transmission but are at increased risk of tuberculosis, which could potentially be prevented through identification and treatment of latent infection in close collaboration with a pre-entry screening programme.FundingWellcome Trust, UK National Institute for Health Research, UK Medical Research Council, Public Health England, and Department of Health Policy Research Programme.

Housing and tuberculosis in an Inuit village in northern Quebec: a case-control study.

Between November 2011 and November 2012, an Inuit village in Nunavik, Quebec experienced a surge in the occurrence of active TB; contact investigations showed that TB infection was highly prevalent (62.6%), particularly among those over age 14 years (78.8%). A nested case-control study showed that nutritional inadequacy was associated with acquisition of infection but not progression to disease. We performed a study to determine whether characteristics of one's dwelling were associated with 1) acquisition of newly diagnosed TB infection and 2) progression to confirmed or probable disease among those with TB infection. In this nested case-control study, we enrolled 200 people who were household or social contacts of at least 1 person with active TB or had received a diagnosis of active TB and assessed whether characteristics of their dwellings were associated with their odds of having newly diagnosed TB infection and/or odds of progression to disease between November 2011 and November 2012. For our first objective, we compared participants with newly diagnosed TB infection (regardless of their disease status) to a control group of contacts who were uninfected. For the second objective, we compared participants with confirmed or probable disease to a control group consisting of those with infection but no disease. We used information collected during investigation of the contacts and from study questionnaires to determine whether participants may have been exposed to TB in their own home (if they had shared a dwelling with someone who had smear-positive TB during the outbreak) or in other dwellings that they visited at least weekly. The participants lived in 79 dwellings. The mean number of people per room was 1.1 (standard deviation [SD] 0.5). The mean room size and ventilation level of the common living space (kitchen and living/dining rooms) were 67.9 (SD 9.4) m3 and 1.69 (SD 0.26) air changes per hour, respectively. After adjustment for potential confounders, the number of people per room was positively associated with the odds of newly diagnosed infection and odds of disease, but only among participants who lived with someone with smear-positive TB (the minority of participants). Other dwelling characteristics were not associated with either outcome. Reducing household crowding may contribute to TB prevention. Overall, our investigations have not identified associations that explain the elevated disease risk in this village. In light of our results and considering the high prevalence of TB infection, treatment of latent infection is an essential intervention for long-term reduction of TB incidence in this village.

Improving Completion Rates for Therapy of Latent Tuberculosis

An important component in the strategy to eliminate tuberculosis is the treatment of latent infection (LTBI). However, completing such therapy is a

Improving Control of Tuberculosis in Low-Burden Countries: Insights from Mathematical Modeling

Tuberculosis control and elimination remains a challenge for public health even in low-burden countries. New technology and novel approaches to case-finding, diagnosis, and treatment are causes for optimism but they need to be used cost-effectively. This in turn requires improved understanding of the epidemiology of TB and analysis of the effectiveness and cost-effectiveness of different interventions. We describe the contribution that mathematical modeling can make to understanding epidemiology and control of TB in different groups, guiding improved approaches to public health interventions. We emphasize that modeling is not a substitute for collecting data but rather is complementary to empirical research, helping determine what are the key questions to address to maximize the public-health impact of research, helping to plan studies, and making maximal use of available data, particularly from surveillance, and observational studies. We provide examples of how modeling and related empirical research inform policy and discuss how a combination of these approaches can be used to address current questions of key importance, including use of whole-genome sequencing, screening and treatment for latent infection, and combating drug resistance.

OsdR of Streptomyces coelicolor and the Dormancy Regulator DevR of Mycobacterium tuberculosis Control Overlapping Regulons.

Two-component regulatory systems allow bacteria to respond adequately to changes in their environment. In response to a given stimulus, a sensory kinase activates its cognate response regulator via reversible phosphorylation. The response regulator DevR activates a state of dormancy under hypoxia in Mycobacterium tuberculosis, allowing this pathogen to escape the host defense system. Here, we show that OsdR (SCO0204) of the soil bacterium Streptomyces coelicolor is a functional orthologue of DevR. OsdR, when activated by the sensory kinase OsdK (SCO0203), binds upstream of the DevR-controlled dormancy genes devR, hspX, and Rv3134c of M.tuberculosis. In silico analysis of the S.coelicolor genome combined with in vitro DNA binding studies identified many binding sites in the genomic region around osdR itself and upstream of stress-related genes. This binding correlated well with transcriptomic responses, with deregulation of developmental genes and genes related to stress and hypoxia in the osdR mutant. A peak in osdR transcription in the wild-type strain at the onset of aerial growth correlated with major changes in global gene expression. Taken together, our data reveal the existence of a dormancy-related regulon in streptomycetes which plays an important role in the transcriptional control of stress- and development-related genes. IMPORTANCE Dormancy is a state of growth cessation that allows bacteria to escape the host defense system and antibiotic challenge. Understanding the mechanisms that control dormancy is of key importance for the treatment of latent infections, such as those from Mycobacterium tuberculosis. In mycobacteria, dormancy is controlled by the response regulator DevR, which responds to conditions of hypoxia. Here, we show that OsdR of Streptomyces coelicolor recognizes the same regulatory element and controls a regulon that consists of genes involved in the control of stress and development. Only the core regulon in the direct vicinity of dosR and osdR is conserved between M.tuberculosis and S.coelicolor, respectively. Thus, we show how the system has diverged from allowing escape from the host defense system by mycobacteria to the control of sporulation by complex multicellular streptomycetes. This provides novel insights into how bacterial growth and development are coordinated with the environmental conditions.

What can we offer to 3 million MDRTB household contacts in 2016?

The diagnosis of multidrug resistant tuberculosis (MDR-TB) in any individual is the beginning of a prolonged and difficult therapeutic journey. It also marks the moment from which to begin consideration of how to manage close contacts. Preventive therapy for drug-susceptible latent tuberculosis infection has been demonstrated to be effective at reducing the risk of future disease; the stakes are higher when considering prevention of MDR-TB because treatment of active disease is more prolonged and toxic and much less effective. This has encouraged exploration of the potential utility of preventive therapy, with second-line agents, in reducing future incident drug-resistant TB.Three clinical trials of preventive therapy for contacts of patients with MDR-TB are starting in 2015/16; results will not be available until at least 2020, so what should be offered to exposed contacts in the interim?A recent policy brief, arising from a global consultation meeting of international experts, recommended preventive therapy based upon very limited available observational data. However the many known unknowns associated with this approach, include the high proportion of index-contact pairs with discordant drug susceptibility profiles and (even if susceptibilities are shared) the lack of data supporting the use of the selected agents in the treatment of latent infection (rather than active disease).It is important to acknowledge that the alternative to offering preventive therapy is not doing nothing. On the contrary, identified contacts should be maintained under close, active surveillance for 24 months, enabling early detection of active disease in the small proportion amongst whom this may occur. Such patients should benefit from less extensive disease at diagnosis and early access to individualized therapeutic regimens with improved treatment outcomes. Moreover the vast majority of contacts that do not develop disease will benefit from avoidance of potentially toxic, unnecessary therapy.Whether preventive therapy or close observation are implemented, national programmes should maintain a register of all contacts, interventions and 24 month outcomes; these will provide important performance metrics for programmatic management of MDRTB. If harmonized and standardized internationally, such a register could rapidly yield a wealth of observational data, to complement the trial results of the future.

Latent Tuberculosis Infection Screening and 2-Year Outcome in Antiretroviral-Naive HIV-Infected Patients in a Low-Prevalence Country.

Diagnosis and treatment of latent tuberculous infection decrease the incidence of tuberculosis (TB) in HIV-infected patients. To evaluate the diagnostic yield of two IFN-γ release assays and tuberculin skin testing for the screening of latent infection in HIV-infected patients. We performed a prospective study in 29 referral centers for HIV care in France. Asymptomatic, antiretroviral-naive patients infected with HIV-1 who consented to participate underwent two commercial tests (T-SPOT.TB and QuantiFERON-TB Gold In-Tube ELISA test [QFT]) and skin test at enrollment and were followed up for clinical events during 24 months. Between March 2009 and 2011, 506 patients were included, of whom 415 performed the three tests. Median age was 38 years (interquartile range, 31-45 yr), with median CD4 cell count of 466/μL (337-615 μL), and HIV viral load of 4.5 log10 copies/ml (3.6-4.9 log10 copies/ml). At least one IFN-γ release assay was positive for 55 (13.5%) patients: QFT (n = 43), T-SPOT.TB (n = 34), both (n = 22). Skin test was positive (>5 mm) in 66 (15.9%) patients, with intertest agreement at 81 to 86%. On multivariate analysis, positive IFN-γ release assay was only correlated with country of birth (8.4% for France vs. 17.9% for high-prevalence countries, P = 0.004). Of the 55 patients with positive IFN-γ release assay, 8 (14.5%) developed active TB, all within 120 days. No other case of active TB was diagnosed. Once active TB was excluded, IFN-γ release assay-based latent infection prevalence was 11.8%. Systematic screening for latent TB infection by IFN-γ release assay identifies a population at high risk of active TB over the next months. An extensive diagnostic work-up for active TB must follow positive IFN-γ release assay, before considering treatment of latent infection. Clinical trial registered with www.clinicaltrials.gov (NCT00805272).

Tuberculosis

Tuberculosis (TB) resulted in 1.3 million deaths and 8.6 million new cases of active TB worldwide in 2012. Clinical manifestations of TB include fever, night sweats, weight loss, and cough. Latent infection is established by a positive tuberculin skin test or interferon-γ-release assay. Active TB disease is diagnosed by clinical, radiographic, and laboratory findings. Latent infection treatment is recommended in at-risk populations. The standard initial regimen for active disease includes rifampin, isoniazid, pyrazinamide, and ethambutol. Health-care providers are encouraged to consult with a TB specialist for assistance in the management of individuals with suspected or confirmed TB.

The epidemiology of childhood tuberculosis in the Netherlands: still room for prevention.

BackgroundThe occurrence of tuberculosis (TB) among children has long been neglected as a public health concern. However, any child with TB is a sentinel event indicating recent transmission. Vaccination, early case finding and treatment of those latently infected with TB can prevent cases, severe morbidity and unnecessary death.MethodThe objective of the study was to describe the occurrence of TB events among children in the Netherlands which may be avoided through preventive measures. For this purpose we performed a trend analysis of routine Dutch TB and LTBI (surveillance data in 1993–2012 and a descriptive analysis of children with TB and with LTBI diagnosed in 2005–2012).ResultsOverall childhood TB incidence has declined over the last two decades from 3.6 in 1993 to 1.9 per 100,000 children in 2012. The decline was stronger among Dutch-born children compared to foreign-born children. In 2005–2012 64% of childhood TB cases were detected through active case finding. Foreign-born children with TB were less likely to be detected through active case finding, when not detected through post-entry TB screening. Childhood TB diagnosis was culture confirmed in 68% of passively detected cases and 12% of actively detected cases. Of 1,049 children with LTBI started on preventive treatment in 2005–2012, 90% completed treatment. In 37% of all childhood TB cases there was at least one ‘missed opportunity’ for prevention. Thirty nine percent of child TB patients eligible for BCG were not vaccinated.ConclusionChildren with TB in the Netherlands are generally detected at an early stage and treatment completion rates are high. However, more TB cases among children can be prevented through enhancing TB case finding and screening and preventive treatment of latent TB infection among migrant children, and improving the coverage of BCG vaccination among eligible risk groups.

Tuberculosis: Current state of knowledge

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has developed various mechanisms to survive and cause disease in the human host. Incomplete understanding of the complex microbe-host interactions has hindered the identification of suitable biomarkers to expedite the development of diagnostic tools, drugs and vaccines. The field effectiveness of directly observed therapy-short course has been compromised by the intrinsic limitations of sputum microscopy and suboptimal adherence to the long duration of treatment amid the HIV-TB syndemic and various socioeconomic constraints. While molecular tools are transforming the diagnostic processes, especially for multi-drug-resistant (MDR)-TB, drug development and service provision for MDR-TB seriously lag behind. Inappropriate management of detected MDR-TB cases may amplify drug resistance, jeopardizing future control. Targeted screening and treatment of latent infection with M. tuberculosis with the currently available immunodiagnostic tools and treatment regimens aim more for personal protection than major epidemiological impact or elimination. The interferon-γ release assays (IGRA) are not affected by cross-reaction to the bacillus Calmette-Guérin (BCG) vaccine and are increasingly used for such screening before initiation of biologics for treatment of rheumatoid arthritis and other autoimmune disorders. BCG offers only partial and unreliable protection against pulmonary TB in adults, the crucial transmission link for this airborne infection. Systems biology and vaccinomics may speed up vaccine research. The successful development of a fully effective TB vaccine that targets both growing bacteria and non-growing persisters may reflect a major breakthrough, as natural infection does not induce sufficient immunity to prevent reinfection.