A protocol for a systematic review and meta-analysis of tuberculosis care around the time of pregnancy.

Background: Tuberculosis is estimated to cause 1.5 million deaths annually and is most common during the reproductive years. Despite that fact, we found that tuberculosis screening, prevention or care recommendations for people around the time of pregnancy were absent from some national policy recommendations and varied in others. Objectives: To address the apparent gaps and inconsistencies in policy, we aim to design a systematic review and meta-analysis of the original research evidence informing tuberculosis care around the time of pregnancy. Methods: With assistance from librarians at the Biomedical library of the University of Gothenburg, Pubmed, CINAHL and Scopus databases will be searched. Search terms will aim to identify studies generating original research evidence informing care for tuberculosis around the time of pregnancy. Evidence may include: the outcome of TB and/or of pregnancy; the cost-effectiveness or acceptability of any intervention; the sensitivity and specificity of any assessment, selection, diagnostic or test criterion. The output from these literature searches will be screened by two independent reviewers to select the eligible studies for inclusion. Discrepancies will be resolved with a third reviewer. Firstly, publications that provide contextual data will be tabulated, summarising their main contributions. Secondly, studies that provide evidence directly guiding patient care will be our focus and will be considered to be key. The key studies will be subject to quality assessment, data extraction and when possible, meta-analysis. Conclusions: This systematic review and meta-analysis aims to guide policy, practice and future research priorities concerning tuberculosis care around the time of pregnancy.

Tuberculosis is a leading infectious cause of death and is most common during the reproductive years. To address gaps and inconsistencies in policy, we aim to review original research evidence informing tuberculosis care around the time of pregnancy. Evidence may include: the outcome of TB and/or the outcome of pregnancy; the cost-effectiveness or acceptability of any intervention; the reliability (sensitivity and specificity) of any assessment, selection, diagnostic or test criterion. First, publication databases (Pubmed, CINAHL and Scopus) will be searched to identify evidence. The output from these literature searches will then be screened to select eligible studies Next, publications that provide contextual data will be tabulated, summarising their main contributions. After this, studies that provide evidence directly guiding patient care will be our focus and will be considered to be key. The key studies will be subject to formal quality assessment, data extraction and when possible, meta-analysis to assess and summarise their findings. In conclusion, this systematic review and meta-analysis aims to guide policy, practice and future research priorities concerning tuberculosis care around the time of pregnancy.

Perceived barriers to the uptake of health services among first-year university students in Johannesburg, South Africa.

BACKGROUND: Young people face many barriers to accessing appropriate health care services including screening for HIV and tuberculosis (TB). The study aimed to identify perceived barriers to the uptake of health services among young adults entering the tertiary education system in South Africa. METHODS: We conducted a cross-sectional study among first-year students aged 18-25 years, registered at one of three universities in Johannesburg, South Africa, in 2017. Participants completed a self-administered paper-based questionnaire. We describe perceived barriers to accessing health services, stratified by gender and recent engagement in TB or HIV services, together with sources of information about HIV and TB. RESULTS: Seven hundred and ninety-two (792) students were included in the study of which 54.8% were female. Perceived barriers to accessing services included long waiting time (n = 342,43.2%), attitude of health workers (n = 263,33.2%), lack of sufficient information/poor health literacy (n = 148,18.7%), and inability to leave/stay away from studies (n = 137,17.3%). Among participants who tested for HIV in the past 6 months (n = 400, 50.5%), waiting time and attitude of health care workers were perceived as barriers to accessing services. Compared to males, females were more likely to view attitudes of health workers (40.3% vs. 25.0%; p = 0.001) and inability to leave/stay away from studies (20.5% vs.13.4%; p = 0.025) as potential barriers. While just over half of the students (50.5%; 400/792) in this study had accessed health services in the past 6 months, very few (15.0%) opted to use campus health services, and even less (5%) reported receiving information about HIV and TB from the university itself. CONCLUSION: Despite perceived barriers to accessing HIV and TB services off campus, fewer than one in five students starting out at university opted to use campus health services. Campus health services could address many of the barriers unique to university students.

Increased risk of hepatotoxicity and temporary drug withdrawal during treatment of active tuberculosis in pregnant women.

BACKGROUND: Few studies have focused on the treatment of tuberculosis (TB) during pregnancy. This study aimed to evaluate the risk of adverse events, particularly liver toxicity, in pregnant women during treatment for active TB. METHODS: We conducted a retrospective study on pregnant and age-matched non-pregnant women receiving treatment for active TB at four hospitals in Western Sweden between 1992 and 2017. RESULTS: A total of 135 women were included, 40 pregnant and 95 non-pregnant. The frequency of severe hepatotoxicity was 40% in pregnant women and 6% among non-pregnant women (p < 0.001) (odds ratio 9.9; 95% confidence interval 3.5-28.0). Temporary drug withdrawal due to elevated transaminase levels was more frequent for pregnant than non-pregnant women (40% vs 9.5%; p < 0.001) (odds ratio 6.4; 95% confidence interval 2.5-16.2). There was one fatal case of hepatotoxicity in a pregnant woman. CONCLUSION: Severe hepatotoxicity was significantly more frequent in pregnant women compared to non-pregnant women. Careful monitoring of liver transaminases while receiving TB treatment during pregnancy is mandatory, as well as ensuring adequate measures with adjustment of drug regimen and temporary drug withdrawals when a rise in liver enzymes is noted.

Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants.

OBJECTIVETo determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children.DESIGNIndividual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.METHODSWe searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.RESULTSProbiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25-0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23-0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11-4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is ≥5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89-1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89-1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.CONCLUSIONSModerate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%.TRIAL REGISTRATIONPROSPERO 2015 identifier: CRD42015015701Infect Control Hosp Epidemiol 2018;771-781.

Social and behavioral factors associated with failing second-line ART - results from a cohort study at the Themba Lethu Clinic, Johannesburg, South Africa.

Poor adherence is a main challenge to successful second-line ART in South Africa. Studies have shown that patients can re-suppress their viral load following intensive adherence counselling. We identify factors associated with failure to re-suppress on second-line ART. The study was a retrospective cohort study which included HIV-positive adults who experienced an elevated viral load ≥400 copies/ml on second-line ART between January 2013-July 2014, had completed an adherence counselling questionnaire and had a repeat viral load result recorded within 6 months of intensive adherence counselling. Log-binomial regression was used to evaluate the association between patient characteristics and social, behavioral or occupational factors and failure to suppress viral load (≥400 copies/ml). A total of 128 patients were included in the analysis, and of these 39% (n = 50) failed to re-suppress their viral load. Compared to those who suppressed, far more patients who failed to suppress reported living with family (44.2% vs. 23.7%), missing a dose in the past week (53.3% vs. 30.0%), using traditional/herbal medications (63.2% vs. 34.3%) or had symptoms suggestive of depression (57.7% vs. 34.3%). These patient-related factors could be targeted for interventions to reduce the risk for treatment failure and prevent switching to expensive third-line ART.

Tbc kan påvisas med PCR ­ men bara i direktpositiva luftvägsprov.

TB can be detected with PCR - but only in smear-positive respiratory samples Unnecessary and inappropriate clinical requests represent a great waste of time and money and may also result in false diagnoses. PCR-techniques, such as Cobas TaqMan MTB, are used for rapid detection of tuberculosis (TB).  These assays are only validated for respiratory specimens, but they are commonly requested also for non-respiratory specimens.  These assays perform well in smear-positive respiratory samples, while the sensitivities are quite unsatisfactory for both respiratory and non-respiratory smear-negatives samples. The specificity is high and it is possible to rapidly distinguish between TB and infections caused by environmental mycobacteria. The analyses demonstrate, furthermore, that PCR assays cannot be used to evaluate treatment, detect relapses or exclude TB. Nor can these assays be used to evaluate contagiousness or to screen for TB.

Predictive and prognostic properties of TB-LAM among HIV-positive patients initiating ART in Johannesburg, South Africa.

While the diagnostic properties of the TB LAM urine assay (LAM) have been well-described, little is known about its predictive and prognostic properties at ART initiation in a routine clinic setting. We describe the predictive and prognostic properties of LAM in HIV-positive patients initiating ART at an urban hospital in Johannesburg, South Africa. Retrospective study of HIV-positive adults (>18 years) who initiated standard first-line ART between February 2012 and April 2013 and had a LAM test at initiation. In HIV-positive patients with no known TB at ART initiation, we assessed the sensitivity, specificity and positive/negative likelihood ratios of LAM to predict incident TB within 6 months of ART initiation. In addition, in patients with a TB diagnosis and on TB treatment <3 months at ART initiation, we measured the CD4 response at 6 months on ART. Of the 274 patients without TB at ART initiation, 65% were female with median CD4 count of 213 cells/mm(3). Among the 14 (5.1%) patients who developed active TB, none were urine LAM +ve at baseline. LAM had poor sensitivity (0.0% 95% CI 0.00-23.2) to predict incident TB within 6 months of initiation. We analyzed 22 patients with a confirmed TB diagnosis at initiation separately. Of these, LAM +ve patients (27%) showed lower CD4 gains compared to LAM negative patients (median increase 103 vs 199 cells/mm(3); p = 0.08). LAM has limited value for accurately predicting incident TB in patients with higher CD4 counts after ART initiation. LAM may help identify TB/HIV co-infected patients at ART initiation who respond more slowly to treatment and require targeted interventions to improve treatment outcomes. Larger studies with longer patient follow-up are needed.

Tuberculosis-related knowledge is associated with patient outcomes in shantytown residents; results from a cohort study, Peru.

OBJECTIVES: Tuberculosis is frequent among poor and marginalized people whose limited tuberculosis-related knowledge may impair healthcare access. We characterised tuberculosis-related knowledge and associations with delayed treatment and treatment outcome. METHODS: Tuberculosis patients (n = 943), people being tested for suspected tuberculosis (n = 2020), and randomly selected healthy controls (n = 476) in 16 periurban shantytowns were interviewed characterizing: socio-demographic factors; tuberculosis risk-factors; and patients' treatment delay. Principle component analysis was used to generate a tuberculosis-related knowledge score. Patients were followed-up for median 7.7 years. Factors associated with tuberculosis treatment delay, treatment outcome and tuberculosis recurrence were assessed using linear, logistic and Cox regression. RESULTS: Tuberculosis-related knowledge was poor, especially in older people who had not completed schooling and had never been diagnosed with tuberculosis. Tuberculosis treatment delay was median 60 days and was more delayed for patients who were poorer, older, had more severe tuberculosis and in only unadjusted analysis with incomplete schooling and low tuberculosis-related knowledge (all p ≤ 0.03). Lower than median tuberculosis-related knowledge was associated with tuberculosis recurrence (unadjusted hazard ratio = 2.1, p = 0.008), and this association was independent of co-morbidities, disease severity and demographic factors (multiple regression adjusted hazard ratio = 2.6, p = 0.008). CONCLUSIONS: Low tuberculosis-related knowledge independently predicted tuberculosis recurrence. Thus health education may improve tuberculosis prognosis.

Evaluation of the Cobas TaqMan MTB test for detection of Mycobacterium tuberculosis complex.

BACKGROUND: The Cobas TaqMan MTB assay is used for rapid detection of the Mycobacterium tuberculosis complex (MTC) in clinical samples. It is only validated for respiratory samples, but is often requested by physicians for non-respiratory specimens. The aim of this study was therefore to evaluate the performance of this assay in clinical praxis in a country with low prevalence of tuberculosis (TB). METHODS: The results from 2388 respiratory and 1005 non-respiratory human specimens were analyzed by this real-time PCR technique. Using culture results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of the PCR results were calculated. RESULTS: For smear-positive respiratory specimens all the four values investigated were 100%. The number of smear-positive non-respiratory specimens was only eight, and all of these eight specimens reacted positively. Sensitivity was 51% for smear-negative respiratory specimens, and 47% for smear-negative non-respiratory specimens. When all non-respiratory specimens were analyzed together the sensitivity was 51%. Specimens from 16 patients were PCR-positive but culture-negative and these cases are discussed. In one case, TB DNA was still present in sputum 2 years after a successful treatment. CONCLUSION: The study shows that the Cobas TaqMan MTB assay performs well in smear-positive samples, while the sensitivities are unsatisfactory for both respiratory and non-respiratory smear-negative specimens. Furthermore, the analyses emphasize that this assay cannot be used to evaluate treatment or contagiousness, or to detect relapses or screen for TB.

Effects of probiotic intake and gender on nontyphoid Salmonella infection.

GOALS: The goal of the study was to examine if intake of Lactobacillus plantarum can accelerate clearance of nontyphoid Salmonella and reduce infection-related symptoms. BACKGROUND: Nontyphoid Salmonella is a major cause of gastroenteritis worldwide. Few studies have explored the effect of probiotics in these infections. STUDY: Patients with Salmonella infection were randomized to daily intake of 5 × 10 colony forming units of freeze-dried Lactobacillus plantarum 299 v or placebo. Symptoms were recorded daily. Feces were cultured weekly. Treatment continued until 4 consecutive stool cultures negative for Salmonella had been obtained. RESULTS: The treatment and placebo groups did not differ significantly with regard to time to clearance of Salmonella, or time to resolution of symptoms. Irrespective of treatment, women tended to clear Salmonella more rapidly than men (19 vs. 28 d, P=0.18), despite a longer diarrheal phase (5 vs. 3 days after inclusion, P=0.001). After Salmonella clearance (postinfectious phase), women experienced loose stools, nausea, and flatulence more frequently than men. In women, L. plantarum treatment was associated with more abdominal pain, whereas in men L. plantarum treatment reduced the prevalence of hard stools, and increased the presence of diarrheal symptoms in the postinfectious phase. CONCLUSIONS: Gender, but not administration of the probiotic strain L. plantarum 299 v, may influence acute symptoms during Salmonella infection and possibly clearance of Salmonella. Symptoms in the postinfectious phase were modified by the probiotics in a gender-specific way, but our results give little support for positive effects of L. plantarum 299 v treatment in nontyphoid salmonellosis.

Oral and faecal lactobacilli and their expression of mannose-specific adhesins in individuals with and without IgA deficiency.

Lactobacilli are present in the intestine and oral cavity of most adults. Secretory IgA in mucosal secretions may provide carbohydrate receptors for bacterial adhesins. Here, oral and faecal samples from 33 IgA-deficient individuals and 34 controls were cultured for lactobacilli, which were identified using species-specific PCR or partial 16S rDNA sequencing and tested for expression of mannose-specific adhesins. Lactobacilli were found in the oral cavity of 76% of IgA-deficient and 85% of control individuals. Lactobacillus paracasei and Lactobacillus gasseri dominated in both groups. Lactobacillus fermentum was less common in IgA-deficient individuals than in controls (p=0.0055) and Lactobacillus salivarius was less common in symptomatic than in healthy IgA-deficient individuals (p=0.0051). Faecal samples yielded lactobacilli in most individuals. L. paracasei was most frequent, followed by L. gasseri and Lactobacillus plantarum. Mannose-specific adhesins were expressed more frequently by oral than by faecal isolates (p=0.032) and oral isolates adhered in higher numbers than faecal isolates (46 vs. 14 bacteria/cell, p=0.0038). Faecal isolates from IgA-deficient individuals more frequently expressed mannose-specific adhesins than faecal isolates from controls (p=0.039). Mannose-specific adhesins may be a colonisation factor in the oral cavity, and the presence of secretory IgA may modify adhesin expression. However, secretory IgA seems to have little influence on Lactobacillus species distribution.

Intake of Lactobacillus plantarum reduces certain gastrointestinal symptoms during treatment with antibiotics.

GOALS: To examine if intake of Lactobacillus plantarum can prevent gastrointestinal side effects in antibiotic-treated patients. BACKGROUND: Diarrhea is a common side effect of treatment with antibiotics. Some studies indicate that the risk of antibiotic-associated diarrhea can be reduced by administration of certain probiotic microorganisms. STUDY: Patients treated for infections at a university hospital infectious diseases clinic were randomized to daily intake of either a fruit drink with L. plantarum 299v (10(10) colony forming units/d) or a placebo drink, until a week after termination of antibiotic treatment. Subjects recorded the number and consistency of stools as well as gastrointestinal symptoms until up to 3 weeks after last intake of test drink. Fecal samples were collected before the first intake of test drink and after termination of antibiotic therapy and analyzed for Clostridium difficile toxin. RESULTS: Clinical characteristics on admission were similar in the 2 groups. The overall risk of developing loose or watery stools was significantly lower among those receiving L. plantarum [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.52-0.92; P=0.012], as was development of nausea (OR, 0.51; 95% CI, 0.30-0.85; P=0.0097). Diarrhea defined as > or =3 loose stools/24 h for > or =2 consecutive days was unaffected by the treatment (OR, 1.4; 95% CI, 0.33-6.0; P=0.86). No significant differences regarding carriage of toxin producing C. difficile were observed between the groups. CONCLUSIONS: Our results indicate that intake of L. plantarum could have a preventive effect on milder gastrointestinal symptoms during treatment with antibiotics.

Lactobacilli in the intestinal microbiota of Swedish infants.

Lactobacillus colonisation was examined in 112 Swedish infants. Faecal samples obtained at 1, 2, 4 and 8 weeks and at 6, 12 and 18 months of age were cultivated quantitatively on Rogosa agar. Lactobacilli were speciated by PCR and typed to the strain level by randomly amplified polymorphic DNA (RAPD). Lactobacilli reached a peak at 6 months when 45% of the infants were colonised. L. rhamnosus and L. gasseri were the most common species in this period. Colonisation by lactobacilli in general (P < 0.01) and L. rhamnosus in particular (P < 0.05) was more common in breast-fed than in weaned infants at 6 months of age. Lactobacillus isolation reached a nadir of 17% by 12 months (P < 0.0001), but increased to 31% by 18 months of age P < 0.05). The food-related species L. paracasei, L. plantarum, L. acidophilus and L. delbrueckii dominated in this second phase. A single strain persisted for at least 3 weeks in 17% of the infants during the first 6 months, most commonly L. rhamnosus. Lactobacillus population counts in colonised infants increased from 10(6.4) cfu/g at 1 week to 10(8.8) cfu/g at 6 months, and then dropped to 10(5.4) cfu/g faeces at 12 months of age. Lactobacillus colonisation was not significantly related to delivery mode, or to presence of siblings or pets in the household. Our results suggest that certain Lactobacillus species, especially L. rhamnosus, thrive in the intestinal flora of breast-fed infants. After weaning they are replaced by other Lactobacillus species of types found in food.