Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. RESULTS: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. CONCLUSIONS: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction.

BACKGROUND: Throughout the COVID-19 pandemic, testing individuals remains a key action. One approach to rapid testing is to consider the olfactory capacities of trained detection dogs. METHODS: Prospective cohort study in two community COVID-19 screening centers. Two nasopharyngeal swabs (NPS), one saliva and one sweat samples were simultaneously collected. The dog handlers (and the dogs…) were blinded with regards to the Covid status. The diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction was assessed as compared to nasopharyngeal RT-PCR as the reference standard, saliva RT-PCR and nasopharyngeal antigen testing. RESULTS: 335 ambulatory adults (143 symptomatic and 192 asymptomatic) were included. Overall, 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/143) or in asymptomatic participants (31/192). The overall sensitivity of canine detection was 97% (95% CI, 92 to 99) and even reached 100% (95% CI, 89 to 100) in asymptomatic individuals compared to NPS RT-PCR. The specificity was 91% (95% CI, 72 to 91), reaching 94% (95% CI, 90 to 97) for asymptomatic individuals. The sensitivity of canine detection was higher than that of nasopharyngeal antigen testing (97% CI: 91 to 99 versus 84% CI: 74 to 90, p = 0.006), but the specificity was lower (90% CI: 84 to 95 versus 97% CI: 93 to 99, p = 0.016). CONCLUSIONS: Non-invasive detection of SARS-CoV-2 infection by canine olfaction could be one alternative to NPS RT-PCR when it is necessary to obtain a result very quickly according to the same indications as antigenic tests in the context of mass screening.

Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial.

BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. METHODS: The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18-45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%). This trial is registered with ClinicalTrials.gov, NCT04872075. FINDINGS: Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit. Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements. The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09-0·40) and three of the 1947 non-attendees (0·15%; 0·03-0·45; absolute difference, 95% CI -0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint. INTERPRETATION: Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2-transmission risk, provided a comprehensive preventive intervention was implemented. FUNDING: French Ministry of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Predicting the risk of respiratory distress in newborns with congenital pulmonary malformations.

OBJECTIVES: Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation. METHODS: MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping. RESULTS: In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (>37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max <0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability. CONCLUSIONS: Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres.

Evaluation of a saliva molecular point of care for the detection of SARS-CoV-2 in ambulatory care.

Rapid identification of SARS-CoV-2-infected individuals is a cornerstone for the control of virus spread. The sensitivity of SARS-CoV-2 RNA detection by RT-PCR is similar in saliva and nasopharyngeal swabs. Rapid molecular point-of-care tests in saliva could facilitate, broaden and speed up the diagnosis. We conducted a prospective study in two community COVID-19 screening centers to evaluate the performances of a CE-marked RT-LAMP assay (EasyCoV) designed for the detection of SARS-CoV2 RNA from fresh saliva samples, compared to nasopharyngeal RT-PCR, to saliva RT-PCR and to nasopharyngeal antigen testing. Overall, 117 of the 1718 participants (7%) tested positive with nasopharyngeal RT-PCR. Compared to nasopharyngeal RT-PCR, the sensitivity and specificity of the RT-LAMP assay in saliva were 34% and 97%, respectively. The Ct values of nasopharyngeal RT-PCR were significantly lower in the 40 true positive subjects with saliva RT-LAMP (Ct 25.9) than in the 48 false negative subjects with saliva RT-LAMP (Ct 28.4) (p = 0.028). Considering six alternate criteria for reference tests, including saliva RT-PCR and nasopharyngeal antigen, the sensitivity of saliva RT-LAMP ranged between 27 and 44%. The detection of SARS-CoV-2 in crude saliva samples with an RT-LAMP assay had a lower sensitivity than nasopharyngeal RT-PCR, saliva RT-PCR and nasopharyngeal antigen testing.Registration number: NCT04578509.

Accuracy of saliva and nasopharyngeal sampling for detection of SARS-CoV-2 in community screening: a multicentric cohort study.

Nasopharyngeal sampling for nucleic acid amplification testing (NAAT) is the standard diagnostic test of coronavirus disease 2019. Our objectives were to assess, in real-life conditions, the diagnostic accuracy of a nasopharyngeal point-of-care antigen (Ag) test and of saliva NAAT for detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in ambulatory care. This was a prospective cohort study from 19 October through 18 December 2020 in two community COVID-19 screening centers in Paris, France. Two nasopharyngeal swabs and one saliva sample were simultaneously collected. Diagnostic accuracies of nasopharyngeal Ag testing and of three saliva NAAT methods were assessed as compared to nasopharyngeal NAAT. A total of 1452 ambulatory children and adults were included. Overall, 129/1443 (9%) participants tested positive on nasopharyngeal NAAT (102/564 [18%] in symptomatic and 27/879 [3%] in asymptomatic participants). Sensitivity was 94%, 23%, 96%, and 94% for the three different protocols of saliva NAAT and for the nasopharyngeal Ag test, respectively. Estimates of specificity were above 95% for all methods. Diagnostic accuracy was similar in symptomatic and asymptomatic individuals. Diagnostic accuracy of nasopharyngeal Ag testing and of saliva NAAT is similar to that of nasopharyngeal NAAT, subject to compliance with specific protocols for saliva. Registration number: NCT04578509.

Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis.

OBJECTIVE: To investigate the relationship of clinical response of Juvenile Idiopathic Arthritis (JIA) to etanercept (ETN) with ETN levels, and the presence of anti-drug antibodies to ETN (ADAb). METHODS: Prospective study of JIA patients under 18 years old. Clinical and pharmacological data were collected at two visits. JIA clinical inactivity and activity were assessed according to the Wallace criteria and to the Juvenile Arthritis Disease Activity Score (JADAS). ETN and ADAb serum levels assessments were determined using ELISA-based assays. RESULTS: 126 patients were enrolled. The median duration of ETN treatment at inclusion was 569 days (range 53-2340). ADAb were undetectable (<10 ng/ml) in 171/218 (78%) samples and were > 25 ng/mL in 2/218 samples. No significant relationship between ETN concentration and the clinical inactivity status and JIA activity was found using either univariate logistic regression or multiple logistic regression analysis, adjusted on one individual descriptors, time since diagnosis, time of sampling, use of corticosteroids or methotrexate and classification of JIA. No correlation was found between the remission status and the detection of ADAb. CONCLUSION: This study did not demonstrate any correlation between JIA activity and circulating ETN levels in a large population of patients with JIA previously treated with ETN for at least 1.5 months. As described for adults, our study confirms that ETN is marginally immunogenic in pediatric patients. These results do not support the clinical usefulness of a monitoring of ADAb or ETN concentrations for the management of this group of JIA patients if they fail to achieve clinical inactive disease.

Sofosbuvir plus daclatasvir with or without ribavirin for chronic hepatitis C infection: Impact of drug concentration on viral load decay.

BACKGROUND: Sofosbuvir (SOF) plus daclatasvir (DCV) with or without ribavirin is one of the currently recommended treatment option for chronic hepatitis C. AIMS: Our objectives were to identify factors associated with SOF/DCV plasma concentrations [C] variations and to evaluate their impact on viral kinetics. METHODS: 130 consecutive HCV patients initiating SOF/DCV therapy with or without ribavirin were enrolled. Clinical, biological, virological and pharmacological data were collected at baseline, at week 4, 8, 12, and 24 of therapy and 12 weeks after the end of therapy. RESULTS: Mean age was 57 years, 68% of patients were males, 69% were infected by HCV genotype 1 and cirrhosis was observed in 76% of patients. Multivariate analysis showed that higher SOF [C] and DCV [C] during treatment were associated with eGFR impairment and absence of cirrhosis. We found a significant correlation between the magnitude of HCV viral load decrease from day 0 to week 4 and a higher SOF [C] at week 4 (p=0.032) and a higher DCV [C] at week 8 (p=0.013). CONCLUSIONS: Pharmacological monitoring showed significant associations between elevated SOF or DCV [C] and absence of cirrhosis, decreased eGFR and viral load decrease during the first month of treatment.