Positive Skin Test Research Articles

Latent tubercolosis infection in the migrant population: an Italian surveillance experience

Abstract Background The Special Reception Center (“Centro Accoglienza Straordinario” or CAS in Italian) concept was born in Italy in 2014 to receive the large number of migrants arriving in Italy. There are around 3100 centres are in Italy, of which 200+ in Tuscany. Each Center’s objective is to support migrants’ social integration through Italian language and job orientation courses. On arrival at a facility, migrants undergo diagnostic and lab tests to highlight potentially infectious diseases; among these, tuberculosis is one of the most frequently encountered. Therefore, the objective of the study is to estimate the prevalence of Latent Tuberculosis Infections (LTBIs) among migrants hosted in CAS centers. Methods From May-December 2023, Amiata Senese, Val d’Orcia and Valdichiana Senese Public Health Unit staff, according to national and departmental guidelines, implemented a number of health surveillance protocols, with close attention to latent tuberculosis infection. This protocol includes the Mantoux TB skin test at the CAS: in case of positivity, subjects are directed to further exams (chest X-ray, TB-IGRA blood test, infectious disease specialist consultation) in order to implement a therapy. Results From May-December 2023, 259 migrants (241 males and 18 females) received the TB skin tests. Average subject age was 26. Pakistan was the most represented nation of origin with 130 migrants (50%), followed by Bangladesh (9.7%) and Ivory Coast (7.3%). 77 migrants showed a positive TB skin test result (29.7%): of these 56 (i.e. 21.6% of the migrants screened) were also positive to the TB-IGRA blood test and treated for LTBI. Conclusions The high prevalence of LTBIs found in the referenced CAS indicates the need to continue/extend these surveillance protocols. Implementing successfully this procedure requires the involvement of a range of professionals from the socio-health sector within a process necessarily coordinated by the Disease Prevention Department. Key messages • Screening and surveillance of infectious diseases among migrant population represent a major public health issue for European health systems. • Detection and treatment of Latent Tubercolosis Infections require a multiprofessional and integrated approach, coordinated by the Disease Prevention Department.

Rank correlation between atopic comorbidity and laboratory parameters in allergic rhinitis

One of the current cutting-edge problems in allergy and ENT is the study of comorbidity in allergic rhinitis, which is the most common atopic disease among all other atopies. Two decades ago, a new endotype of the disease, local allergic rhinitis, was discovered. In the past, some patients with typical complaints of chronic nasal congestion, persistent runny nose, and other similar symptoms, did not display such characteristic diagnostic criteria as positive allergy skin tests and an increased value of serum total IgE and specific IgE antibodies. They were qualified by allergists and ENT specialists as individualists with non-allergic rhinitis and, accordingly, did not receive adequate treatment. However, their symptoms remained, prompting them to abuse decongestants and resulting in an increased burden on the cardiovascular system. This, along with the burden of concomitant pathology, including other atopies, can be considered a significant medical and social problem. With the purpose to study rank correlation between comorbidity and three laboratory biomarkers, 46 patients with allergic rhinitis were examined. The list of parameters included two routine items such as serum total IgE and eosinophilic cationic protein, and rarely studied IL-4 in skin exudate. Clinical analysis showed that significantly more often allergic rhinitis in patients was combined with bronchial asthma (in 39.1%, p 0.05), less often with food allergy (in 19.6%), atopic dermatitis (in 10.9%), insect allergy (in 8.7%), and allergic urticaria (in 4.5%). In one case, local perennial rhinitis was identified, accompanied by conventional seasonal rhinitis with a high content of serum total IgE and positive allergic skin tests with pollen allergens. Skin tests with household allergens, including house dust mite products, showed a negative result. This case was regarded as a manifestation of the so-called “double” allergic rhinitis. The Spearman correlation demonstrated a negative mean strength relationship between comorbidity and serum IgE and eosinophilic cationic protein (p 0.05). The seemingly paradoxical result can be interpreted quite logically, taking into account immunopathogenetic mechanisms of allergic inflammation. In particular, with an increase in the frequency of atopic comorbidity, the migration of eosinophils from the blood to sites of eosinophilic inflammation increases.

Relevance of the basophil activation test in a cohort of 240 patients with chronic spontaneous urticaria.

Basophil activation test (BAT) is considered to be the best biomarker to predict autoimmune chronic spontaneous urticaria (aiCSU). To date, few studies have investigated the utility of BAT in real-life clinical practice, the role of aiCSU biomarkers in relation to omalizumab therapy and the association between aiCSU tests. This study aimed to analyze the clinical and laboratory features of a prospective cohort with CSU according to their BAT status, as well as to study omalizumab efficacy according to aiCSU biomarkers. A prospective study was conducted from 2010 to 2024 in patients with CSU. BAT alongside other laboratory tests were performed, and clinical and therapeutic features were prospectively collected. Data obtained was compared according to BAT status. Furthermore, omalizumab drug survival was typified according to aiCSU biomarkers. A total of 240 patients were included in the study. BAT positive patients presented more frequently low IgE levels, higher occurrence of IgG anti-thyroid peroxidase (anti-TPO) positivity, autologous serum skin test (ASST) positivity, basopenia, and eosinopenia. The multivariate logistic regression revealed that ASST (OR:7.69, 95%CI: 2.81-21.0) and anti-TPO (OR:2.63, 95%CI: 1.05-6.61) were associated to BAT positivity. All aiCSU biomarkers (BAT, ASST, combined ASST/BAT positivity and low IgE/anti-TPO+) associated significantly shorter omalizumab survival due to failure. In the cohort, both low IgE/anti-TPO+ and ASST were concordant and associated to BAT. The use of BAT in clinical practice delineates a subgroup of patients with specific clinical, laboratory and therapeutic features, including increased omalizumab failure.

Evaluation of cephalosporin allergy - A survey amongst drug allergy experts

BackgroundSince publication of the 2022 Drug Allergy Practice Parameters (DAPP) of the AAAAI and ACAAI it is unclear the extent to which the simplified and risk-stratified evaluation of cephalosporin allergy has been incorporated into allergy practice. ObjectiveWe aimed to assess current cephalosporin allergy testing practices using real case examples. MethodsAn 18-question REDCap survey was sent to the 136 members of the Adverse Reactions to Drugs, Biologics and Latex (ARDBL) Committee of the AAAAI between February-April 2023. ResultsForty-six (33.8%) ARDBL members completed the survey, following three email attempts. Most practicing in the United States (32, 69.6%), six (13.0%) in Canada, and the remaining from Europe and Asia. Almost half (47.7%) reported that the 2022 DAPP had increased their use of direct oral challenges. 91% would use cephalosporins in the setting of low-risk penicillin allergy history without testing. For low-risk cephalosporin reactions, 68% would perform a direct oral challenge (DOC) with the culprit drug. In severe immediate penicillin reactions, 23% would evaluate with penicillin-skin-testing before assessing cephalosporin allergy. For cephalosporin-related anaphylaxis, 48% would perform cephalosporin-based testing. For perioperative anaphylaxis with cefazolin, 57% would perform cephalosporin-based testing. For positive skin testing to cefazolin 79% chose to avoid the culprit drug with follow-up oral challenge to a structurally dissimilar cephalosporin. ConclusionIncreased uptake of DOC represents the initial impact of the 2022 DAPP. However, there is significant variation in testing practices of cephalosporin allergy even amongst drug allergy experts, reflecting a need for higher evidence base to guide consensus around testing higher risk reactions.

Allergic reactions to enzyme replacement therapy in children with lysosomal storage diseases and their management.

Human recombinant enzyme replacement therapy, given to compensate for genetic enzyme deficiency in lysosomal storage diseases, delays the progression of the disease and improves the quality of life. However, enzyme replacement therapy may cause hypersensitivity reactions. Within the scope of this research, we aimed to elucidate the frequency and clinical features of hypersensitivity reactions against enzyme replacement therapy in children with lysosomal storage diseases and clarify the management of these reactions. Medical records of pediatric patients with lysosomal storage disease and receiving enzyme replacement therapy were retrospectively reviewed, and patients who experienced allergic reactions were included in the study. The demographic characteristics of the patients, their diagnosis, the responsible enzyme, the time at which the reaction started and at what dose, the signs and symptoms associated with the reaction, diagnostic tests, the management of the reaction, and the protocol applied for the maintenance of enzyme replacement therapy after the reaction were recorded. Hypersensitivity reactions developed in 18 of 71 patients (25.3 %) who received enzyme replacement therapy. The most common cutaneous findings were observed. Anaphylaxis developed in 6 of 18 patients. Patients who experienced recurrent hypersensitivity reactions with premedication or a slower infusion rate, those with positive skin test results, and patients who developed anaphylaxis were given enzyme replacement therapy with desensitization. HSR may develop during enzyme replacement therapy, which are vital in lysosomal storage diseases, and discontinuation of enzyme replacement therapy is a significant loss for patients with metabolic disorders. These reactions can be treated with premedication and long-term infusions, but some patients may require desensitization protocols for continued treatment.

A study of autologous serum therapy in patients of chronic urticaria at a tertiary care center in western India

Background: Chronic urticaria (CU) is a common and troublesome dermatosis for patients. Approximately 30-50% of patients with CU have an autoimmune basis for their condition, as shown by a positive skin test for ASST, this subgroup is known as Autoreactive chronic urticaria. autologous serum therapy (AST) is considered a potential curative for this auto-reactive subgroup. Our study aimed to find out the efficacy of AST in both ASST positive and ASST negative CU patients. Methods: A cohort of 100 patients of CU were prospectively analyzed for incidence of ASST (+) patients out of total and efficacy of autologous serum injections for sequential 6 weeks in both ASST (+) and ASST (-) CU patients. The response of AST was recorded by the urticaria total severity scale (TSS) every week for 6 weeks and at 18 weeks. Results: The mean baseline TSS in the ASST (+) group was 12.14±1.66 and in the ASST (-) group was 11.77±1.45 (p-value- 0.5). The mean TSS at 18 weeks in the ASST (+) group was 1.30±1.51 and in the ASST (-) group was 2.17±2.02 (p-value-0.151). At 18 weeks of treatment, complete clearance was present in 44.6% of the ASST (+) group and 31.4% in the ASST (-) group (p value-0.151). Conclusions: AST can be considered as a first line of treatment, in patients of CU irrespective of the results of ASST, which is cost-effective and has long-lasting effects.

Manifestation of ocular tuberculosis in a north Indian tertiary care centre: Case series

Ocular tuberculosis acts as a challenge throughout the world, and its pathophysiology, diagnosis, and treatment are a topic for debate. The present case series represents retrospective study focusing on the variable clinical presentations, the diagnostic and therapeutic characteristics of ocular tuberculosis. We report 12 patients of ocular tuberculosis with variable presentations. : Retrospective analysis of records of patients diagnosed with ocular tuberculosis from August 2022 till March 2023 was done. Diagnosis of ocular tuberculosis was based on detailed ocular and systemic examination including best corrected visual acuity (BCVA), Slit lamp examination, fundus examination, OCT. The patients presenting with features suggestive of ocular tuberculosis were further investigated with complete blood count (CBC), erythrocyte sedimentation rate (ESR), Monteaux test, Chest X-ray, Cartridge Based Nuclear Amplification Test (CBNAAT) and rheumatological work up. Out of 12 of ocular tuberculosis patients, 4 were diagnosed with active retinal vasculitis, 3with choroiditis, 3 had panuveitis, and remaining 2 patients had unilateral nodular episcleritis. The diagnosis was based on compatible clinical picture, highly positive Tuberculin skin test and dramatic response to anti-tuberculous drugs. All 12 cases were strongly Mantaux test positive (2 developed injection site ulceration). All cases were started on ATT immediately with pulmonologist consultation and showed clinical improvement after 1 month. Ocular tuberculosis can have myriad presentations. Positive Mantaux test plays an important role in supporting diagnosis of ocular tuberculosis.

Tuberculin Skin Test Reactivity among Health Care Workers in the Abia State University Teaching Hospital, Aba South-east Nigeria

Background Tuberculosis is one of the infections targeted for eradication and is still under surveillance. Hospital workers in Nigeria take little or no precautions against tuberculosis while attending to patients. Objectives This research aimed to study the prevalence of the reactivity of positive Tuberculin Skin Tests among healthcare workers in a Nigerian University Teaching Hospital. Methods Ethical approval and informed consent were obtained from the participants. Two hundred and ten consented participants were recruited for this study, while 185 contributed till the end. The Tuberculin Skin Test was conducted following the standard operating procedures. The chi-square test was used to compare the variable at a significant level of P < 0.05. Of those who received a BGC vaccine < 3 years, 4.8% were excluded from the analyses. Results Mean ± SD of participants’ age was approximately 30 ± 8 years. Participants comprised 87 (47%) males and 98 (53%) females. The modal age group was 21-25 years. Most participants were clinical medical students, 93(50.3%), while doctors, 7 (3.8%), were second to least. The prevalence of positive reactivity to the Tuberculin Skin Test was 29.9%. There was no significant difference observed regarding sexes and positive reactivity. A significant difference was found in reactivity ≥ 10 mm between those who didn’t receive BCG and those who received BCG vaccine ≥ 10 years before the study. Conclusion Healthcare workers can be potential active TB patients and reservoirs. We recommend highly sensitive and specific periodic TB screening, prophylactic treatment, and re-vaccination of Health Care Workers in Nigeria.

Contribution of Gestational Weight Gain to Childhood Asthma Phenotypes: A Prospective Cohort Study

BackgroundThe contribution of prenatal anthropometric measures to the development of specific childhood asthma phenotypes is not known. ObjectiveWe aimed to evaluate associations between prepregnancy body mass index (BMI) and gestational weight gain (GWG) with allergic and non-allergic asthma phenotypes in childhood. MethodsOur study population included term, healthy infants in the middle Tennessee region of the United States. Prepregnancy BMI and GWG were ascertained from questionnaires administered during early infancy and categorized based on World Health Organization (WHO) and Institute of Medicine (IOM) recommendations, respectively. Allergic asthma was defined as 5-year current asthma and a positive skin test or specific IgE to aeroallergen(s). We used multivariable logistic regression models for asthma and multinomial logistic regression models for non-asthma, allergic asthma, and non-allergic asthma. ResultsA total of 1,266 children were included. At the 5-year follow-up, 194 (15.3%) had asthma; among them, 102 (52.6%) had allergic asthma. Both inadequate and excessive GWG, compared to adequate GWG, were associated with increased odds of asthma (inadequate: aOR 1.76 [95% CI: 1.03–2.98]; excessive: aOR 1.70 [95% CI: 1.12–2.57]) and increased odds of allergic asthma compared to no asthma (inadequate: aOR 3.49 [95% CI: 1.66–7.32]; excessive: aOR 2.55 [95% CI: 1.34–4.85]). Prepregnancy BMI was not associated with asthma nor with asthma phenotypes. ConclusionBoth inadequate and excessive GWG were associated with allergic asthma risk. These results support the benefits of optimal GWG during pregnancy on child health outcomes.

Overlooked, dismissed, and downplayed: reversion of Mycobacterium tuberculosis immunoreactivity.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Following infection, immune responses to Mtb antigens can be measured using the tuberculin skin test or an interferon-γ release assay. The gain of Mtb immunoreactivity, a change from a negative to a positive tuberculin skin test or interferon-γ release assay result, is called conversion and has long been used as a measure of Mtb exposure. However, the loss of immunoreactivity (reversion; a positive followed by a negative result) has often been overlooked. Instead, in clinical and epidemiological circles, Mtb immunoreactivity is commonly considered to persist lifelong and confer a lifetime of disease risk. We present a critical review, describing the evidence for reversion from cohort studies, ecological studies and studies of TB progression risk. We outline the inconsistent reasons why reversion has been dismissed from common understanding and present evidence demonstrating that, just as conversion predominantly indicates prior exposure to Mtb antigens, so its opposite, reversion, suggests the reduction or absence of exposure (endogenous or exogenous). Mtb immunoreactivity is dynamic in both individuals and populations and this is why it is useful for stratifying short-term TB progression risk. The neglect of reversion has shaped TB research and policy at all levels, influencing clinical management and skewing Mtb infection risk estimation and transmission modelling, leading to an underestimation of the contribution of re-exposure to the burden of TB, a serious oversight for an infectious disease. More than a century after it was first demonstrated, it is time to incorporate reversion into our understanding of the natural history of TB.

Early testing and grade of the reaction are affecting factors of skin test positivity in β-Lactam allergies.

Background: β-Lactams are the most widely used antibiotic family in the world. Nevertheless, they also stand out as the primary culprits for inducing drug hypersensitivity reactions (HSR). Methods: Between May 2018 and March 2023, patients with suspected HSRs to β-lactams, who underwent skin tests (ST), were retrospectively screened. The determinants of allergenic penicillin (DAP) tests, which include penicillin minor and major determinants, clavulanic acid, and amoxicillin, along with ampicillin, sulbactam, the identified culprit drugs, and alternative cephalosporins, which include cefuroxime, ceftriaxone prick and/or intradermal tests, were administered. The analysis focused on identifying positive ST results and determining the true HSRs rates in this patient cohort. Results: Of the 147 patients, 78.9% (n = 116) were women and the median (minimum-maximum) age was 41 years (18-71 years). Mild HSRs (grades 1-2) were observed in 72.78% (n = 107), whereas 24.4% (n = 36) had severe reactions (grades 3-4) and 2.7% (n = 4) had an unknown grade. Of the patients, 64% (n = 94) experienced HSRs within the first hour after the last dose of the identified culprit drug. The overall positivity rate for all STs was 26.5% (n = 39). ST positivity rates were notably higher in individuals who had experienced HSRs within the past 6 months (p = 0.02) and those with severe anaphylaxis (p < 0.001). Conclusion: β-Lactam ST positivity is higher, especially in those with grades 3-4 reactions and consulted a physician within the first 6 months after their HSRs.

A case of solitary choroidal tuberculoma with highly positive tuberculin skin test and negative interferon gamma release assays.

A case of solitary choroidal tuberculoma with highly positive tuberculin skin test and negative interferon gamma release assays.

Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosis.

Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe TB diseases. Tuberculin skin test (TST) is commonly used for TB diagnosis, but its accuracy in neonates is influenced by various factors, including bacilli Calmette-Guérin (BCG) vaccination. This study aimed to identify predictors of positive TSTs in neonates exposed to HCWs with pulmonary TB. A retrospective observational study was conducted to compare the frequency of predictors between TST-positive and TST-negative neonates. Demographic, epidemiological, and clinical data of neonates exposed to TB, along with that of HCW and household contacts, were collected retrospectively through contact investigations with the Korean National TB Surveillance System (KNTSS) database. TSTs using 2 tuberculin units of purified protein derivative RT23 were performed on exposed neonates at the end of preventive TB treatment. Firth logistic regression was performed to identify predictors of TST positivity. Contact investigations revealed that 152 neonates and 54 HCWs were exposed to infectious TB index cases in 3 neonatal care facilities. Of 152 exposed neonates, 8 (5.3%) had positive TST results. Age of 6 days or more at the initial exposure is a statistically significant predictor of positive TST (Firth coefficient 2.1, 95% confidence interval 0.3-3.9, P = 0.024); BCG vaccination showed no statistical significance in both univariable and multivariable analysis. Sex, prematurity, exposure duration, duration from initial exposure to contact investigation, and isoniazid preventive treatment duration were not significant predictors. Age at the initial exposure is a significant predictor of positive TST in neonates exposed to active pulmonary TB. Given the complexities of TST interpretation, including false positives due to BCG vaccination, careful risk assessment is necessary for appropriate decision-making and resource allocation in the management of neonatal TB exposure.

Impact of allergic rhinitis on quality of life in patients with chronic rhinosinusitis

ObjectivesTo evaluate the impact of allergic rhinitis (AR) on the quality of life (QoL) in patients with chronic rhinosinusitis (CRS). MethodsRetrospective cross-sectional study of adult patients with CRS presenting to our clinic between August 2020 and February 2023 was performed. AR was diagnosed based on a positive skin or blood allergy test. Patients' characteristics, AR status, comorbidities, endoscopy scores, and SNOT-22 scores were collected. ResultsA total of 514 CRS patients were included, with 265 (51.6 %) patients with AR. CRS patients with AR were younger (p = 0.004), more likely to be female (p < 0.001), and more likely to have asthma (p < 0.001). Polyp status and endoscopy scores did not differ between patients with and without AR. Baseline SNOT-22 scores were slightly worse in the AR cohort (43.6 vs 38.7, p = 0.007), which was mainly secondary to rhinologic (p = 0.002), extrarhinologic (p = 0.007), and ear/facial (p = 0.007) subdomains. Worse rhinologic and extrarhinologic scores were associated with the presence of AR after adjusting for confounding variables (Coef = 1.55, p = 0.011; and Coef = 0.83, p = 0.021 respectively). ConclusionThe impact of allergic rhinitis on QoL is mainly on the nasal symptoms. Further studies should look at the role of AR on the QoL of different CRS endotypes; and at the role of AR-specific treatment, such as immunotherapy, on the QoL of patients with CRS.

Prospective, Multicenter, Head-to-Head Comparison Between Allergists Versus Nonallergists in Low-Risk Penicillin Allergy Delabeling: Effectiveness, Safety, and Quality of Life (HK-DADI2)

BackgroundPenicillin “allergy” labels are prevalent but frequently misdiagnosed. Mislabelled allergies are associated with adverse outcomes and increased antimicrobial resistance. With an urgent need to delabel the overwhelming number of mislabelled allergies, non-allergist evaluations have been advocated for low-risk individuals. Despite growing interest in non-allergist-led initiatives; evidence on their effectiveness, safety, and impact by direct comparisons are lacking. ObjectiveWe assessed the comparative outcomes of penicillin allergy evaluations conducted by allergists vs. non-allergists. MethodsA prospective, multi-centre, pragmatic study was conducted at four tertiary hospitals (one allergist- vs. three non-allergist-led) for low-risk penicillin allergy patients in Hong Kong – the Hong Kong Drug Allergy Delabelling Initiative 2 (HK-DADI2). ResultsAmong 228 low-risk patients who underwent testing (32.9% by allergists, 67.1% by non-allergists), only 14 (6.1%) had positive penicillin allergy testing. Delabelling rates (94.1% vs. 93.3%, p=0.777), positive skin tests (2.6% vs. 2.7%, p=1.000) and drug provocation tests (3.3% vs. 2.7%, p=1.000) were similar between allergists and non-allergists. There were no systemic reactions in either cohort. All patients had significant improvements in health-related quality-of-life (DrHy-Q scores −5.00 vs. −8.33, p=0.072). Non-allergist evaluations had shorter waiting times (0.57 vs. 15.7 months, p<0.001), while allergists required fewer consultations with higher rate of completing evaluations within a single-visit (OR=0.04, p<0.001). ConclusionWith training and support, non-allergists can independently evaluate low-risk penicillin allergies. Compared to allergists, evaluation of low-risk penicillin allergy by non-allergists can be comparably effective, safe, and impactful on quality-of-life. More multi-disciplinary partnerships to empower non-allergists to conduct allergy evaluations, should be encouraged.

Specific IgE and Basophil Activation Test by Microarray: A Promising Tool for Diagnosis of Platinum Compound Hypersensitivity Reactions.

Drug hypersensitivity reactions (DHRs) to platinum-based compounds (PCs) are on the rise, and their personalized and safe management is essential to enable first-line treatment for these cancer patients. This study aimed to evaluate the usefulness of the basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PCs. A total of 24 patients with DHRs to PCs (20 oxaliplatin and four carboplatin) were evaluated: thirteen patients were diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients were diagnosed as non-allergic with negative STs and DPTs, and five patients were classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. The BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarray were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control groups were negative for sIgE- and BAT-microarray. Our experience indicated that the sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PCs and may provide an advance in decision making for drug provocation testing.

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial

Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. Canadian Institutes of Health Research.

Exhaled and Systemic Biomarkers to Aid the Diagnosis of Bronchial Asthma in Elite Water Sports Athletes.

Our aim was to evaluate the accuracy of a combined airway inflammatory biomarker assessment in diagnosing asthma in elite water sports athletes. Members of the Hungarian Olympic and Junior Swim Team and elite athletes from other aquatic disciplines were assessed for asthma by objective lung function measurements, and blood eosinophil count (BEC), serum total immunoglobulin E (IgE), fractional exhaled nitric oxide (F ENO ) measurements, and skin prick testing were performed. A scoring system from BEC, F ENO , serum IgE, and skin test positivity was constructed by dichotomizing the variables and assigning a score of 1 if the variable is elevated. These scores were summed to produce a final composite score ranging from 0 to 4. A total of 48 participants were enrolled (age 21 ± 4 yr, 42% male), of which 22 were diagnosed with asthma. Serum total IgE and F ENO levels were higher in asthmatic individuals (68 [27-176] vs 24 [1-43], P = 0.01; 20 [17-26] vs 15 [11-22], P = 0.02), and positive prick test was also more frequent (55% vs 8%, P < 0.01). Asthmatic participants had higher composite variable scores (2 [1-3] vs 1 [0-1], P = 0.02). Receiver operating characteristic analysis showed that total IgE, F ENO , and composite variable were suitablefor identifying asthmatic participants (area under the curve = 0.72, P = 0.01; 0.70, P = 0.02, and 0.69, P = 0.03). A composite score of >2 reached a specificity of 96.2%, a sensitivity of 36.4%, and a likelihood ratio of 9.5. Logistic regression model revealed a strong association between the composite variable and the asthma diagnosis (OR = 2.71, 95% confidence interval = 1.17-6.23, P = 0.02). Our data highlight the diagnostic value of combined assessment of Th2-type inflammation in elite water sports athletes. The proposed scoring system may be helpful in ruling in asthma in this population upon clinical suspicion.

Management of newborns and healthcare workers exposed to isoniazid-resistant congenital tuberculosis in the neonatal intensive care unit

Management of newborns and healthcare workers (HCWs) exposed to congenital tuberculosis (TB) in the neonatal intensive care unit (NICU) has been reported rarely. To outline a contact investigation process for individuals exposed to congenital TB in the NICU and investigate nosocomial transmission. Additionally, to assess the efficacy and safety of window prophylaxis in exposed newborns. A baby, born at a gestational age of 28+ 1 weeks, was diagnosed with isoniazid-resistant congenital TB on the 39th day of admission to the level IV NICU. Newborns and HCWs exposed cumulatively for ≥8h underwent contact investigation and follow-up for a year. Eighty-two newborns underwent contact investigation. All newborns displayed normal chest X-rays, and 42 hospitalized newborns tested negative for acid-fast bacilli stain and Xpert® MTB/RIF assay in their endotracheal sputum or gastric juices. Eighty received window prophylaxis: six of 75 on rifampin experienced mild adverse events, and none of the five on levofloxacin. After 12 weeks, five (6.1%) had a positive tuberculin skin test, all of whom had already received the Bacillus Calmette-Guérin vaccine and tested negative on TB interferon-gamma releasing assay. Of 119 exposed HCWs, three (2.5%) were diagnosed with latent TB infection and completed a four-month rifampin therapy. There was no active TB disease among exposed newborns and HCWs during a one-year follow-up. Timely diagnosis of congenital TB is crucial for minimizing transmission among exposed neonates and HCWs in the NICU setting. In cases of isoniazid-resistant index patients, even premature newborns may consider the use of rifampin or levofloxacin for window prophylaxis.

Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection.

Tuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, Mycobacterium tuberculosis, can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to Mycobacterium tuberculosis and activin A as a biomarker of ongoing disease.