Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children.

BACKGROUND: Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure. METHODS: Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored. RESULTS: The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001). CONCLUSIONS: The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy. TRIAL REGISTRATION: Current Controlled Trials Identifier NCT00948896.

Quality of life in adolescents with asthma, during the transition period from child to adult.

AIM: The present investigation was designed to evaluate the health-related quality of life (HRQOL) of adolescents with asthma between the age of 16 and 21, when they are transferred from paediatric to adult care. METHODS: In this prospective study, 156 teenagers (69 females) with asthma were screened employing spirometry, a histamine challenge, skin prick test for allergy and filled out the 'Living with Asthma Questionnaire' both at the time of entry into the study and after 2 and 5 years of follow-up. An exercise test and questions concerning regular performed exercise were carried out at baseline and 5 years later. RESULTS: At all three time-points, the HRQOL of the men was generally better than that of the women. At the same time, the HRQOL of both genders was significantly better, both in terms of the overall scores (P < 0.001) as well as the scores for most of the individual domains, in connection with the 5-year follow-up. The young women who exercised regularly at the time of their entry exhibited better HRQOL at this time than those who did not (P < 0.001), whereas regular exercise had no impact on the HRQOL of the young men. The women with severe asthma demonstrated a poorer HRQOL than those suffering from mild-to-moderate asthma. CONCLUSION: The HRQOL of adolescents with asthma improves with age. The pronounced positive correlation between regular exercise and HRQOL in female adolescents with asthma revealed here deserves special attention in the care of young women and deserves further exploration.

Adolescents with asthma: consequences of transition from paediatric to adult healthcare.

PURPOSE: A prospective follow-up of adolescents with asthma designed to identify risk factors for deterioration during and after transfer from paediatric to adult healthcare. METHODS: Adolescents (n=150) with asthma being transferred from paediatric to adult healthcare were recruited consecutively and those with mild/moderate asthma assigned randomly to primary care or specialized care at an adult asthma clinic. Tests of pulmonary function, bronchial responsiveness and working capacity and skin prick tests were performed at the time of entry into the study and two and/or five years later. RESULTS: Initially, 88.7% of the subjects demonstrated at least one positive skin prick test. During the five-year follow-up, FEV(1) improved, while FEV(1)/FVC remained unchanged. Bronchial hyperresponsiveness was present in 71% of the subjects at the time of inclusion and 59% five years later, while 20 developed hyperresponsiveness during this period. Poor adherence to treatment, female gender and inhalation of steroids exerted negative impacts on logPD(20). The risk for persistence of bronchial hyperresponsiveness was elevated by poor adherence and attenuated by regular exercise. The decline observed in working capacity demonstrated no correlation to the risk factors examined. Subjects with mild/moderate asthma who received primary or specialized care exhibited similar pulmonary function, responses to a histamine challenge and working capacities. CONCLUSIONS: During a five-year follow-up of asthmatic adolescents leaving paediatric care, pulmonary function rarely deteriorated, but bronchial hyperresponsiveness persisted. Female gender and poor adherence to treatment exerted negative impact on bronchial hyperresponsiveness. Mild/moderate asthma was managed equally effectively with primary or specialized care.

Long-term non-invasive positive airway pressure ventilation in infants.

AIM: To evaluate the clinical application of long-term non-invasive ventilation (NIV) in infants with life-threatening ventilatory failure with regard to: diagnosis, age at initiation, indication for and duration of treatment, clinical outcome and mortality and adverse effects. PATIENTS AND METHODS: The medical records of 18 infants treated in a home setting during a 7-year period were reviewed. The criteria for ventilatory support were: (a) transcutaneous partial pressures of carbon dioxide (TcPCO(2)) >6.5 kPa and oxygen (TcPO(2)) < 8.5 kPa and (b) decreased cough ability and/or recurrent chest infections. RESULTS: The median age at initiation was 4 months (range 1-12). NIV was initiated because of hypoventilation in 12 infants and because of reduced cough ability and/or recurrent infections in six infants. Tracheotomy was eventually needed in two infants. The median duration of treatment was 24 months (range 1-84). NIV produced significant improvements, with median TcPCO(2) falling from 9.9 to 6.1 kPa, and median TcPO(2) rising from 9.8 to 11.1 kPa. CONCLUSION: NIV can be successfully and safely used in infants with prolonged life-threatening ventilatory failure, potentially avoiding intubation and tracheotomy.

Hypoventilation does not explain the impaired quality of sleep in postpolio patients ventilated noninvasively vs. invasively.

In a previous study, it was found that patients treated with noninvasive ventilation (NIV) reported larger dysfunctions in sleep-related parameters as assessed with the Sickness Impact Profile (SIP) and Health Index questionnaires than those treated with tracheostomy. The aim of the current study was to further evaluate these sleep limitations and relate these limitations to blood gas analyses in the groups to investigate, if the differences could be related to differences in the efficacy of ventilation. We compared postpolio patients treated with tracheostomy (PPT, n = 17), NIV (PPN, n = 14) and patients with neuromuscular disorders treated with NIV (NMN, n = 15). Significantly fewer patients in the PPT group scored large dysfunctions in the SIP sleep (SIP score >10 points) compared with the PPN and NMN patients. The PPT patients scored significantly higher regarding quality of sleep and less sense of tiredness than the PPN and NMN patients. No differences were found between the groups regarding blood gas parameters neither before nor during or after the study period. In conclusion, postpolio patients treated with invasive home mechanical ventilation seem to experience better sleep and less sense of tiredness than patients on NIV. These differences cannot be explained by differences in alveolar ventilation as assessed with blood gas analyses.

Quality-of-life evaluation of patients with neuromuscular and skeletal diseases treated with noninvasive and invasive home mechanical ventilation.

BACKGROUND: Home mechanical ventilation (HMV) is known to be a successful therapy for chronic respiratory insufficiency, with regard to long-term survival. However, the quality of life (QoL) of patients receiving HMV has not previously been systematically investigated. The purpose of this study was to assess the QoL of patients with neuromuscular disorders and skeletal deformities (ie, restrictive lung disease) receiving HMV. METHODS: Patients receiving HMV treated by tracheostomy or noninvasive ventilation (NIV). Three different, standardized, and validated questionnaires were used: the Sickness Impact Profile (SIP), the Health Index (HI), and the Sense of Coherence (SOC) scale. Underlying diseases were postpolio dysfunction (37%), neuromuscular disorder (20%), scoliosis (15%), and other diseases (28%). RESULTS: The group treated with tracheostomy had higher HI scores than the group treated with NIV. For the three main diagnosis groups treated with tracheostomy or NIV, the patients with postpolio dysfunction treated with tracheostomy had lower SIP scores than the patients with postpolio dysfunction treated with NIV. This was in contrast to the patients with neuromuscular disorders treated with tracheostomy, who had higher scores in the SIP, compared with patients with postpolio dysfunction treated with tracheostomy and patients with neuromuscular disorders treated with NIV. A SIP score > 10% indicates a functional disability of clinical importance, and a high score on the HI and SOC scale indicates good perceived health. For the three main diagnosis groups treated with NIV, the patients with scoliosis had no dysfunction of clinical importance (4.6 +/- 3.7) on the SIP score compared with patients with postpolio dysfunction (15.5 +/- 7.6) and patients with neuromuscular disorders (13.2 +/- 5.2) [mean +/- SD]. The men showed more dysfunction in the SIP score than the women. CONCLUSION: Patients receiving HMV reported a good perceived health, despite severe physical limitations. The patients with postpolio dysfunction and the patients with scoliosis treated with tracheostomy perceived the best health, compared with NIV for this diagnosis.