Recent Travel and Tuberculosis in Migrants: Data From a Low-Incidence Country.

Tuberculosis (TB) incidence rates among migrants are higher than those in low-incidence countries. We evaluated smear-positive, pulmonary TB notifications of foreign-born individuals, comparing time since arrival and time since last return travel to the country of origin. TB incidence suggests a time course consistent with recent infection during travel.

Multidrug-resistant tuberculosis: diagnosis, checklists, adverse events, advice and outcomes.

The account of MDR-TB in Finland describes current practice. Genetic testing of primary specimens, whole-genome sequencing, supportive directly observed therapy, checklists and national consilia will contribute to further improvements in managing MDR-TB. https://bit.ly/3rOnb3u.

The monocyte-to-lymphocyte ratio: Sex-specific differences in the tuberculosis disease spectrum, diagnostic indices and defining normal ranges.

BACKGROUND: The monocyte-to-lymphocyte ratio (MLR) has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical value and associations. METHODS: Blood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. Complete blood counts (CBCs) from a multi-ethnic population aged 16 to 65 years were evaluated; a sub-group with normal hematological indices was used to define the range of MLRs. RESULTS: Multivariate analysis in proven tuberculosis (n = 264) indicated MLR associated with low serum albumin, high white cell counts and a positive culture; values were higher in sputum smear-positive pulmonary tuberculosis (S+PTB). Analysis in S+PTB (n = 296) showed higher MLRs in males and those with high neutrophil counts, low serum albumin and high C-reactive protein. The diagnostic value of MLRs was assessed by comparing notified patients with TB (n = 264) with denotified cases (n = 50), active case-finding in non-contacts (TB n = 111 and LTBI n = 373) and contacts of S+PTB (n = 149) with S+PTB found at screening (n = 75). Sensitivities and specificities ranged from 58.0-62.5% and 50.0-70.0% respectively for optimal cut-off values, defined by ROC curves. In CBCs obtained over one month, ratios correlated with neutrophil counts (ρ = 0.48, P<0.00001, n = 14,573; MLR = 0.45 at 8-8.9 x 109/L) and were higher in males than females (P<0.0001). The MLR range (mean ± 2SD) in those with normal hematological indices (n = 3921: females 0.122-0.474; males 0.136-0.505) paralleled LTBI MLRs. Ratios did not predict death (n = 29) nor response to treatment (n = 178 S+PTB with follow-up CBCs). Ratios were higher in males than female in the 16-45 years age group, where immune differences due to sex hormones are likely greatest. CONCLUSIONS: Severe tuberculosis and male sex associated with high MLRs; the same variables likely affect the performance of other biomarkers. The ratio performed poorly as a clinical aid.

Male Sex Bias in Immune Biomarkers for Tuberculosis.

Males have a bias toward developing sputum smear-positive pulmonary tuberculosis, whereas other forms of the disease have an equal sex ratio. Immune responses are known to be affected by estrogen and testosterone. Biomarkers may therefore be affected by these hormones, especially between 16 and 45 years of age when the differences are most marked. Using large data sets, we examined whether the male bias was significant in terms of diagnosis or predictive ability for the development of disease in those exposed to tuberculosis. Despite the large numbers, the need to specify homogeneous population groups for analysis affected the statistical power to discount a useful biomarker. In general, males showed higher interferon-gamma responses to TB antigens ESAT-6 and CFP-10, whilst females had stronger tuberculin responses in those with sputum smear- and culture-positive tuberculosis, but smaller responses in those who were screened for tuberculosis and who did not develop disease. Importantly, in contacts of sputum smear-positive pulmonary tuberculosis, more males who did not develop tuberculosis had tuberculin skin tests in the range between 10 and 14 mm, suggesting that sex-specific cut-offs might be better than general cut-off values for determining who should receive preventive treatment. Immunocytochemistry of the tuberculin responses correlated with cell numbers only in females. Total and anti-lipoarabinomannan IgM antibody levels were lower in males, whereas total and anti-BCG IgE antibody levels were higher. Evaluation of biomarkers should take account of the spectrum of tuberculosis and male sex bias for sputum smear-positive pulmonary tuberculosis. These findings improve our understanding of how immune responses contribute to the pathogenesis of infectious tuberculosis as well as suggesting clinical applications of the differences between the sexes.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Diabetes mellitus and latent tuberculosis infection: baseline analysis of a large UK cohort.

We conducted a cross-sectional analysis of baseline data from a UK cohort study which enrolled participants at risk of latent tuberculosis infection (LTBI, defined as a positive result for either of the two interferon gamma release assays). Binomial regression with a log link was used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the relationship between diabetes mellitus (DM) and LTBI. Adjusted for age, sex, ethnicity, body mass index and the presence of other immunocompromising conditions, DM was associated with a 15% higher prevalence of LTBI (adjusted PR=1.15, 95% CI 1.02 to 1.30, p=0.025). TRIAL REGISTRATION NUMBER: PREDICT is registered on clinicaltrials.gov (NCT01162265).

Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe: A tuberculosis network European Trialsgroup (TBNET) study.

AIM: Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. METHODS: TBNET is a pan-European clinical research collaboration for tuberculosis. An email survey of TBNET members collected data in relation to infection control, access to molecular tests and basic microbiology with drug sensitivity testing. RESULTS: 68/105 responses gave valid information and were from countries within the WHO European Region. Inpatient beds matched demand, but single rooms with negative pressure were only available in low incidence countries; ultraviolet decontamination was used in 5 sites, all with >10 patients with M/XDR-TB per year. Molecular tests for mutations associated with rifampicin resistance were widely available (88%), even in lower income and especially in high incidence countries. Molecular tests for other first line and second line drugs were less accessible (76 and 52% respectively). A third of physicians considered that drug susceptibility results were delayed by > 2 months. CONCLUSION: Infection control for inpatients with M/XDR-TB remains a problem in high incidence countries. Rifampicin resistance is readily detected, but tests to plan regimens tailored to the drug susceptibilities of the strain of Mycobacterium tuberculosis are significantly delayed, allowing for further drug resistance to develop.

Pregnancy in patients with tuberculosis: a TBNET cross-sectional survey.

BACKGROUND: Objectives: To determine whether the incidence of tuberculosis with pregnancy is more common than would be expected from the crude birth rate; to see whether there is significant delay in the diagnosis of tuberculosis during pregnancy. METHOD: Design: A cross-sectional survey. SETTING: 13 tuberculosis clinics within different European countries and the USA. POPULATION/SAMPLE: All patients with tuberculosis seen at these clinics for a period > 1 year. INSTRUMENT: Questionnaire survey based on continuous data collection. MAIN OUTCOME MEASURES: number and proportion of women with tuberculosis who were pregnant; timing of diagnosis in relation to pregnancy, including those who were pregnant or delivered in the 3 months prior to the diagnosis of TB and those who developed TB within 3 months after delivery. RESULTS: Pregnancy occurred in 224 (1.5 %) of 15,217 TB patients and followed the expected rate predicted from the crude birth rate for the clinic populations. TB was diagnosed more commonly in the 3 months after delivery (n = 103) than during pregnancy (n = 68; χ 2 = 25.1, P < 0.001). CONCLUSIONS: TB is diagnosed more frequently after delivery, despite variations in local TB incidence and healthcare systems.

The best of respiratory infections from the 2015 European Respiratory Society International Congress.

The breadth and quality of scientific presentations on clinical and translational research into respiratory infections at the 2015 European Respiratory Society (ERS) International Congress in Amsterdam, the Netherlands, establishes this area as one of the leadings fields in pulmonology. The host-pathogen relationship in chronic obstructive pulmonary disease, and the impact of comorbidities and chronic treatment on clinical outcomes in patients with pneumonia were studied. Various communications were dedicated to bronchiectasis and, in particular, to different prognostic and clinical aspects of this disease, including chronic infection with Pseudomonas and inhaled antibiotic therapy. Recent data from the World Health Organization showed that Europe has the highest number of multidrug-resistant tuberculosis cases and the poorest countries have the least access to suitable treatments. Latent tuberculosis and different screening programmes were also discussed with particular attention to risk factors such as HIV infection and diabetes. Several biomarkers were proposed to distinguish between active tuberculosis and latent infection. Major treatment trials were discussed (REMOX, RIFQUIN and STREAM). The possibility of once-weekly treatment in the continuation phase (RIAQUIN) was especially exciting. The continuing rise of Mycobacterium abscessus as a significant pathogen was noted. This article reviews some of the best contributions from the Respiratory Infections Assembly to the 2015 ERS International Congress.

Chronic cough and a normal chest X-ray - a simple systematic approach to exclude common causes before referral to secondary care: a retrospective cohort study.

Chronic cough is common in the community and can cause significant morbidity. It is not clear how closely treatment guidelines are used in general practice, or how often specialist referral is indicated. We aimed to assess the management of chronic cough in primary care before referral to a cough clinic, and to assess the outcome of managing chronic cough with an approach of simple investigation and empirical treatment trials. Data were extracted from the records of all patients attending a district general hospital respiratory clinic over a two-year period with isolated chronic cough lasting ⩾8 weeks. The clinic assessed symptoms with a cough-severity visual analogue scale and the Leicester Cough Questionnaire. Among 266 patients, the most frequent diagnoses were asthma (29%), gastro-oesophageal reflux (22%) and angiotensin-converting enzyme inhibitor use (14%). In all, 12% had unexplained chronic cough. Common diagnoses had often not been excluded in primary care: only 21% had undergone spirometry, 86% had undergone chest radiography and attempts to exclude asthma with corticosteroids had been made only in 39%. In the clinic few investigations were conducted that were not available in primary care. Substantial improvements in symptoms occurred with a median (interquartile range) total of 2 (2-3) clinic visits. We estimated that 87% of patients could have been managed solely in primary care; we did not identify distinguishing characteristics among this group. Most cases of chronic cough referred to secondary care could be managed with a simple and systematic approach, which is potentially transferrable to a community setting.

Cough and the transmission of tuberculosis.

Cough is a predominant feature of respiratory infection and, in tuberculosis, is of prime importance for transmitting infection. Tuberculosis is transmitted by the air, yet the process by which bacilli are aerosolized has received little attention. Features of cough may account for differences in transmission rates from source cases of pulmonary disease. We review the literature on the mechanisms and characteristics of cough in tuberculosis in the context of the dissemination of infection. Coughing is probably more important than other respiratory maneuvers, and characteristics of mucus may have an important role but data are scarce. Direct mechanisms of cough in tuberculosis are unknown, as are temporal and other patterns that correlate with the release of viable airborne bacilli. Other than antituberculous chemotherapy and masks, there are few methods of modulating cough in tuberculosis. This is an increasingly important area for research.

How to count coughs? Counting by ear, the effect of visual data and the evaluation of an automated cough monitor.

BACKGROUND: Cough causes morbidity and transmits disease yet has been under-researched. The best method for recognising and counting coughs remains unclear. We tested the accuracy of the human ear and measured the influence of visual data on cough counting. We also evaluated PulmoTrack®, a potentially fully-automated cough monitor. METHODS: Consistency amongst listeners and the effect of visual data: Three 14­22-min sequences containing 45­79 coughs were played to 15 respiratory physicians on at least two occasions. Only sound was played on the first occasions but on the final occasion a simultaneous display of audio activity was included. Counts of cough sounds across methods and listeners were compared. Evaluation of PulmoTrack®: 20-h recordings were made from 10 patients with cough. Automated counts were compared with assessment by one investigator. RESULTS: Agreement among listeners was high. The intraclass correlation coefficient (ICC) for cough counts by ear alone was 0.89 (95% CI, 0.65­1.00). With a concurrent visual display of sound amplitude it was 0.94 (0.80­1.00). 4.8% (0.6­9.5) fewer coughs were counted using visual data than by listening alone (mean [SD] total coughs: 190.2 [3.4] vs 200.7 [14.6]; p = 0.04). Cough frequencies reported by PulmoTrack® and the researcher differed substantially (ICC 0.23, −0.51 to 0.34, p = 0.87); PulmoTrack® had a sensitivity of 26% for detecting coughs identified by ear. CONCLUSION: Coughs are well recognised by different listeners. The method used to count coughs should be clearly described as visual information has a significant influence. Non-automated cough counting remains the gold standard method of quantifying cough.

Epitope-specific antibody levels in tuberculosis: biomarkers of protection, disease, and response to treatment.

Monoclonal antibodies restricted to Mycobacterium tuberculosis can measure epitope-specific antibody levels in a competition assay. Immunodominant epitopes were defined from clinical samples and related to the clinical spectrum of disease. Antibody to the immunodominant epitopes was associated with HLA-DR15. Occupational exposure showed a different response and was consistent with recognition of dormancy-related proteins and protection despite exposure to tuberculosis (TB). Studies in leprosy revealed the importance of immune deviation and the relationships between T and B cell epitopes. During treatment, antibody levels increased, epitope spreading occurred, but the affinity constants remained the same after further antigen exposure, suggesting constraints on the process of epitope selection. Epitope-specific antibody levels have a potential role as biomarkers for new vaccines which might prevent the progression of latent to active TB and as tools to measure treatment effects on subpopulations of tubercle bacilli.