Performance of QuantiFERON-TB Gold Plus assays in children and adolescents at risk of tuberculosis: a cross-sectional multicentre study.

INTRODUCTION: The QuantiFERON-TB Gold Plus (QFT-Plus) assay, which features two antigen-stimulated tubes (TB1 and TB2) instead of a single tube used in previous-generation interferon-gamma release assays (IGRAs), was launched in 2016. Despite this, data regarding the assay's performance in the paediatric setting remain scarce. This study aimed to determine the performance of QFT-Plus in a large cohort of children and adolescents at risk of tuberculosis (TB) in a low-burden setting. METHODS: Cross-sectional, multicentre study at healthcare institutions participating in the Spanish Paediatric TB Research Network, including patients <18 years who had a QFT-Plus performed between September 2016 and June 2020. RESULTS: Of 1726 patients (52.8% male, median age: 8.4 years), 260 (15.1%) underwent testing during contact tracing, 288 (16.7%) on clinical/radiological suspicion of tuberculosis disease (TBD), 649 (37.6%) during new-entrant migrant screening and 529 (30.6%) prior to initiation of immunosuppressive treatment. Overall, the sensitivity of QFT-Plus for TBD (n=189) and for latent tuberculosis infection (LTBI, n=195) was 83.6% and 68.2%, respectively. The agreement between QFT-Plus TB1 and TB2 antigen tubes was excellent (98.9%, κ=0.961). Only five (2.5%) patients with TBD had discordance between TB1 and TB2 results (TB1+/TB2-, n=2; TB1-/TB2+, n=3). Indeterminate assay results (n=54, 3.1%) were associated with young age, lymphopenia and elevated C reactive protein concentrations. CONCLUSIONS: Our non-comparative study indicates that QFT-Plus does not have greater sensitivity than previous-generation IGRAs in children in both TBD and LTBI. In TBD, the addition of the second antigen tube, TB2, does not enhance the assay's performance substantially.

Accuracy of Xpert Ultra for the diagnosis of paediatric tuberculosis in a low TB burden country: a prospective multicentre study.

INTRODUCTION: Childhood pulmonary tuberculosis (TB) remains a diagnostic challenge. This study aimed to evaluate the performance of Xpert Ultra for the diagnosis of pulmonary TB in children in a low TB prevalence setting. METHODS: Prospective, multicentre, diagnostic accuracy study. Children with clinical or radiological suspicion of pulmonary TB were recruited at 11 paediatric units in Spain. Up to three gastric or sputum specimens were taken on 3 consecutive days, and analysed by Xpert MTB/RIF, Xpert Ultra and culture in parallel. RESULTS: 86 children were included (median age 4.9 years, IQR 2.0-10.0; 51.2% male). The final diagnosis was pulmonary TB in 75 patients (87.2%); 33 (44.0%) were microbiologically confirmed. A total of 219 specimens, comprising gastric aspirates (n=194; 88.6%) and sputum specimens (n=25; 11.4%), were analysed. Using culture as reference standard and comparing individual specimens, the sensitivity was 37.8% (14/37) for Xpert MTB/RIF and 81.1% (30/37) for Xpert Ultra (p<0.001); specificity was 98.4% (179/182) and 93.4% (170/182), respectively (p=0.02). In the per-patient analysis, considering positive results on any specimen, the sensitivity was 42.9% (9/21) for Xpert MTB/RIF and 81.0% for Xpert Ultra (17/21, p=0.01); specificity was 96.9% (63/65) and 87.7% (57/65, p=0.07), respectively. CONCLUSIONS: In children with pulmonary TB in a low burden setting, Xpert Ultra has significantly higher sensitivity than the previous generation of Xpert assay and only marginally lower specificity. Therefore, in children undergoing evaluation for suspected pulmonary TB, Xpert Ultra should be used in preference to Xpert MTB/RIF whenever possible.

Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial.

Previous clinical trials for drug-susceptible tuberculosis (DS-TB) have shown that first-line treatment with doses of rifampicin up to 40 mg/kg are safe and increase the early treatment response for young adults with pulmonary tuberculosis. This may lead to a shorter treatment duration for those persons with TB and a good baseline prognosis, or increased treatment success for vulnerable subgroups (age > 60, diabetes, malnutrition, HIV, hepatitis B or hepatitis C coinfection, TB meningitis, stable chronic liver diseases). Here, we describe the design of a phase 2b/c clinical study under the hypothesis that rifampicin at 35 mg/kg is as safe for these vulnerable groups as for the participants included in previous clinical trials. RIAlta is an interventional, open-label, multicenter, prospective clinical study with matched historical controls comparing the standard DS-TB treatment (isoniazid, pyrazinamide, and ethambutol) with rifampicin at 35 mg/kg (HR35ZE group) vs. rifampicin at 10 mg/kg (historical HR10ZE group). The primary outcome is the incidence of grade ≥ 3 Adverse Events or Severe Adverse Events. A total of 134 participants will be prospectively included, and compared with historical matched controls with at least a 1:1 proportion. This will provide a power of 80% to detect non-inferiority with a margin of 8%. This study will provide important information for subgroups of patients that are more vulnerable to TB bad outcomes and/or treatment toxicity. Despite limitations such as non-randomized design and the use of historical controls, the results of this trial may inform the design of future more inclusive clinical trials, and improve the management of tuberculosis in subgroups of patients for whom scientific evidence is still scarce. Trial registration: EudraCT 2020-003146-36, NCT04768231.

Clinical and epidemiological characteristics of patients with influenza A (H1N1) 2009 attended to at the emergency room of a children's hospital.

In June 2009, the first influenza pandemic of the twenty-first century, due to the swine origin influenza A (H1N1) 2009 virus, was declared. This study aimed to describe the epidemiological and clinical features, complications, lethality and risk factors for hospital admission of microbiologically confirmed cases of influenza A (H1N1) 2009 infection seen at the emergency department of a children's hospital. All cases of children with influenza A (H1N1) 2009 viral infection, confirmed microbiologically by real-time reverse transcription polymerase chain reactions and treated in the emergency room between July and December 2009, were prospectively included. Patients were compared according to admission requirement to study variables associated with the risk of hospitalisation. Oseltamivir was the antiviral used for the treatment and its safety was analysed. Four hundred and twelve patients with influenza A (H1N1) 2009 infection were included. The most frequent symptoms were: fever (96%), cough (95%) and coryza (90%). Eighty-five patients (20.6%) were admitted: three to the paediatric intensive care unit and two died. Hospitalised children were younger than those not admitted (median age 5 vs 8 years; p = 0.001). Age under 1 year (OR 6.01; CI 95% 2.77-13.05), pneumonia (OR 7.99; CI 95% 3.50-18.22) and haemoglobinopathy or underlying blood disorders (OR 5.99; CI 95% 1.32-27.30) were statistically significant risk factors for admission. No differences were observed regarding onset of antiviral treatment among admitted and non-admitted patients. Treatment with oseltamivir was well tolerated. In conclusion, the incidence of severe cases and lethality of influenza A (H1N1) 2009 infection were low in our setting, even in a population with risk factors for developing complications.

Escherichia coli producing SHV-type extended-spectrum beta-lactamase is a significant cause of community-acquired infection.

OBJECTIVES: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBLEC) is an increasingly significant cause of community-acquired infection worldwide. The epidemiological features of CTX-M- and SHV-producing ESBLEC causing community-acquired infections are compared. METHODS: A multicentre cohort study including all community-acquired infections caused by ESBLEC in four geographical areas of Spain was carried out. ESBL characterization was by isoelectric focusing, PCR and sequencing. Demographics, previous healthcare contact, co-morbidity, use of antimicrobials, invasive procedures and type of infection were collected for all patients. Patients with CTX-M- and SHV-producing isolates were compared using logistic regression. RESULTS: One hundred and twenty-two cases (95% urinary tract infections) were included. ESBLs were characterized in 112 isolates; 77 isolates (69%) produced CTX-M, 36 (32%) produced SHV and 7 (6%) produced TEM enzymes (8 produced >1 ESBL). Patients with isolates producing CTX-M enzymes only (CTX-M group, n = 70) and SHV enzymes only (SHV group, n = 31) were compared. There were no differences in terms of underlying disease, previous healthcare contact, invasive procedures, antibiotic use or type of infection. Multivariate analysis including geographical area showed that a Charlson Index score of >2 (OR = 4.0; 95% CI = 1.2-12.6) was associated with SHV isolates, while age >60 (4.7; 1.7-12.5) was associated with CTX-M isolates. CONCLUSIONS: SHV-producing ESBLEC is a significant cause of community-acquired infection in Spain; the clinical epidemiology of such isolates seems very similar to that of CTX-M-producing E. coli.

Epidemiology and diagnosis of pleural tuberculosis in a low incidence country with high rate of immigrant population: A retrospective study.

BACKGROUND: The confirmatory diagnosis of pleural tuberculosis (pTB) remains challenging. The aim of this study was to describe the clinical and epidemiological characteristics of pTB patients and assess the yield of different diagnostic procedures in a low burden country with a high rate of immigrant population. METHODS: All adult patients with pTB between 2007 and 2014 were studied retrospectively. RESULTS: One hundred and three out of 843 patients with tuberculosis had pTB. Fifty-three (54.1%) were male, and the median age was 45years (range 18-87years). Fifty-two (50.49%) patients were immigrants. A confirmed diagnosis was reached in 16 patients (15.5%) by microbiological studies of pleural effusion. Lung involvement was demonstrated by sputum smear microscopy in 13/49 (26.5%), sputum GeneXpert MTB/RIF test in 13/20 (65%), and sputum culture in 16/37 (43.2%). High-resolution computed tomography (CT) showed lung involvement in 47.7% of the patients. The cure rate was 91.3% at the 1-year follow-up. Three patients died, all of them within the first month after diagnosis. CONCLUSIONS: The detection of lung involvement increased by two-fold when lung CT was used; this correlated with the likelihood of finding a positive microbiological result on sputum sample testing. Pleural microbiological studies had a low diagnostic yield, and sputum could have a complementary role.

Usefulness of FDG PET/CT in the management of tuberculosis.

BACKGROUND: The aim of our study is to describe the FDG-PET/CT findings in patients with tuberculosis and to correlate them with the patient's prognosis. METHODS: We retrospectively collected data from patients with tuberculosis, who had an FDG-PET/CT performed prior to treatment initiation from 2010 to 2015. RESULTS: Forty-seven out of 504 patients with active tuberculosis diagnosis (9.33%) underwent an FDG-PET/CT. The reasons for performing the FDG-PET/CT were: characterization of a pulmonary nodule (24; 51.1%), study of fever of unknown origin (12; 25.5%), study of lymph node enlargement (5; 10.6%) and others (6; 12.8%). Median age was 64 (IQR 50-74) years and 31 (66%) patients were male. Twenty-six (55.3%) patients had an immunosuppressant condition. According to the FDG-PET/CT, 48.6% of the patients had more than 1 organ affected and 46.8% had lymph node involvement. Median SUVmax of the main lesion was 5 (IQR 0.28-11.85). We found an association between the FDG accumulation and the size of the main lesion with a correlation coefficient of 0.54 (p<0.002). Patients with an unsuccessful outcome had a higher ratio SUVmax main lesion / SUVmean liver (1.92 vs 7.67, p<0.02). CONCLUSIONS: In our cohort, almost half of the patients had more than 1 organ affected and 46.8% of them had lymph node involvement. FDG uptake was associated with the size of the main lesion and seems to be related to the treatment outcome. The extent of its potential to be used as an early predictor of treatment success still needs to be defined.

Epidemiology and diagnosis of tuberculous lymphadenitis in a tuberculosis low-burden country.

The aim of this article is to describe epidemiological and clinical data of patients with tuberculous lymphadenitis (TL) and evaluate the yield of the diagnostic techniques employed. Retrospective observational study was performed at the Vall d'Hebron University Hospital, Barcelona, Spain. All adult patients with confirmed TL (microbiologically) or probable TL (suspected by clinical presentation, cyto/histopathological features, and clinical improvement after specific treatment) diagnosed from January 2001 to December 2013 were included. One hundred twenty-two patients were included: 78 (63.9%) patients with confirmed diagnosis and 44 (36.1%) patients with probable TL. Seventy (57.4%) patients were nonnative residents. From 83 fine-needle aspiration (FNA) specimens, 54.8% (40/73) showed granulomatous inflammation, 62.5% (40/64) had positive mycobacterial culture, and 73.3% (11/15) tested positive with Xpert MTB/RIF (Cepheid, Sunnyvale, CA). From 62 biopsy samples, 96.8% (60/62) showed granulomatous inflammation, 64.6% (31/48) had positive mycobacterial culture, and 46.1% (6/13) tested positive with Xpert MTB/RIF. TL has increasingly been diagnosed in our setting, mostly because of cases diagnosed in nonnative residents. FNA is an easy and safe technique for the diagnosis of suspected TL, and the yield regarding mycobacterial culture seems to be similar to the obtained with biopsy. The Xpert MTB/RIF test from FNA specimens may increase the accuracy of the TL diagnosis and provides quicker results.

Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors.

Prolonged viral excretion in immunocompromised hosts leads to long oseltamivir treatment and to the subsequent development of oseltamivir-resistant pandemic influenza virus selection. We report the selection and nasopharyngeal shedding kinetics of an oseltamivir-resistant strain in a hospitalized immunocompromised patient with prolonged influenza illness. Viral load quantification and genotyping methods were performed from 7 serial nasopharyngeal samples. Before initial oseltamivir treatment, the viral load was 5.78 log(10) copies/mL of sample and only wild-type virus population was detected. The nasopharyngeal viral load remained above the detection limit although there was a second course of oseltamivir treatment. Twelve days after the onset of symptoms, an oseltamivir-resistant strain was selected. After 12 days of inhaled zanamivir treatment, the patient was discharged asymptomatic. The study emphasizes the importance of viral load quantification and surveillance of emergence of resistant strains prospectively because the information provided has important implications in the clinical management of the patient.

Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is an increasingly important group of community pathogens worldwide. These organisms are frequently resistant to many of the antimicrobial agents usually recommended for the treatment of infections caused by E coli, such as penicillins, cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole. Data concerning risk factors, clinical features, and therapeutic options for such infections are scarce. METHODS: A case-control study was performed to investigate the risk factors for all types of community-acquired infections caused by ESBL-producing E coli in 11 Spanish hospitals from February 2002 to May 2003. Controls were randomly chosen from among outpatients with a clinical sample not yielding ESBL-producing E coli. The clinical features of these infections were investigated in the case patients. The efficacy of fosfomycin tromethamine and amoxicillin-clavulanate potassium was observationally studied in patients with cystitis. RESULTS: A total of 122 cases were included. Risk factors selected by multivariate analysis included the following: age older than 60 years; female sex; diabetes mellitus; recurrent urinary tract infections (UTIs); previous invasive procedures of the urinary tract; follow-up in outpatient clinic; and previous receipt of aminopenicillins, cephalosporins, and fluoroquinolones. Urinary tract infections accounted for 93% of the cases; 6% of the patients were bacteremic and 10% needed hospitalization. The cure rate of patients with cystitis was 93% with fosfomycin therapy (all isolates were susceptible); among patients treated with amoxicillin-clavulanate, cure rates were 93% for those with susceptible isolates (minimum inhibitory concentration < or =8 microg/mL) and 56% for those with intermediate or resistant isolates (minimum inhibitory concentration > or =16 microg/mL) (P = .02). CONCLUSIONS: In predisposed patients, ESBL-producing E coli is a notable cause of community-acquired infection, and particularly UTI. Fosfomycin and amoxicillin-clavulanate appear to be effective for cystitis caused by susceptible isolates.