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Objectives Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies showed a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. Methods This prospective, multicentre cohort study titled “AutoPilot-Dx”, aimed to validate signature performance and estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. Results In total, 1140 patients were recruited (2/2017–12/2018), of which 1008 met eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with sensitivity of 93.7% (95% CI, 88.7–98.7), specificity of 94.2% (92.2–96.1), positive predictive value of 73.0% (65.0–81.0), negative predictive value of 98.9% (98.0–99.8), and 9.8% equivocal test results. The signature performed consistently across different patient subgroups and detected bacterial immune response in viral PCR positive patients. Conclusions The findings validate high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort and support its potential to reduce antibiotic overuse in children with viral infections. Trial registration Clinicaltrials.gov identifier: NCT03052088.

Bacterial and viral lower respiratory tract infections (LRTIs) are often clinically indistinguishable, leading to antibiotic overuse. We compared the diagnostic accuracy of a new assay that combines 3 host-biomarkers (TRAIL, IP-10, CRP) with parameters in routine use to distinguish bacterial from viral LRTIs. Study cohort included 184 potentially eligible pediatric and adult patients. Reference standard diagnosis was based on adjudication by an expert panel following comprehensive clinical and laboratory investigation (including respiratory PCRs). Experts were blinded to assay results and assay performers were blinded to reference standard outcomes. Evaluated cohort included 88 bacterial and 36 viral patients (23 did not fulfill inclusion criteria; 37 had indeterminate reference standard outcome). Assay distinguished bacterial from viral LRTI patients with sensitivity of 0.93±0.06 and specificity of 0.91±0.09, outperforming routine parameters, including WBC, CRP and chest x-ray signs. These findings support the assay's potential to help clinicians avoid missing bacterial LRTIs or overusing antibiotics.

Salbutamol diskus (SD) and formoterol turbuhaler (FT) are both fast-acting beta(2) agonists delivery systems used to relieve bronchoconstriction, such as that which accompanies acute exacerbations of asthma. Although SD (which is used only on an as-needed basis) is flow independent, the FT (currently recommended for regular therapy) requires a forceful deep inspiration. Thus, the efficacy of FT in children with bronchoconstriction may be inferior to that of SD. We have studied the bronchodilatation response induced by FT after a standard adenosine-5-monophosphate (AMP) bronchial challenge, and compared it to that induced by SD, and placebo. Seventeen children (mean age +/- SD 10.3 +/- 1.7 y) with asthma underwent three AMP challenges, each time followed by inhalation of either placebo, SD (200 mug) or FT (9 mug), in random order. Patterns of bronchodilatation (forced expiratory volume in 1 second recovery) to 90% of baseline levels were compared. Both SD and FT were significantly better than placebo. FT was slightly better than SD, but this difference was not statistically significant. FT and SD are both effective bronchodilators and may be of comparable efficiency during acute bronchoconstriction in young children with asthma.

Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P