Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma.

A subset of patients with asthma is known to have progressive loss of lung function despite treatment with corticosteroids. The aim of the present study was to identify risk factors of decline in forced expiratory volume in one second (FEV(1)) in patients with difficult-to-treat asthma. In total, 136 nonsmoking patients with difficult-to-treat asthma were recruited between 1998 and 1999. Follow-up assessment was performed 5-6 yrs later in 98 patients. The predictive effect of clinical characteristics and inflammatory markers were analysed at baseline (asthma onset and duration, atopy, airway hyperresponsiveness, blood and sputum eosinophils, and the fraction of nitric oxide in exhaled air (F(eNO))) on subsequent decline in post-bronchodilator FEV(1). Patients with high F(eNO) (> or =20 ppb) had an excess decline of 40.3 (95% confidence interval (CI) 7.3-73.2) mL.yr(-1) compared to patients with low F(eNO). F(eNO) > or =20 ppb was associated with a relative risk of 1.9 (95% CI, 1.1-2.6) of having an accelerated (> or =25 mL.yr(-1)) decline in FEV(1). In patients with baseline FEV(1) > or =80% of predicted, this relationship was even stronger: 90 versus 29% had accelerated decline in FEV(1) (F(eNO) > or =20 ppb versus F(eNO) <20 ppb respectively; relative risk 3.1 (95% CI, 1.7-3.4). Exhaled nitric oxide is a predictor of accelerated decline in lung function in patients with difficult-to-treat asthma, particularly if forced expiratory volume in one second is still normal.

Airway inflammation in obese and nonobese patients with difficult-to-treat asthma.

BACKGROUND: Asthma and obesity are associated disorders, but the contribution of obesity to difficult-to-treat asthma as well as the mechanisms responsible for this relationship are unclear. The aim of this study was to investigate the relationship between obesity (body mass index >/= 30) and factors related with asthma severity in patients with difficult-to-treat asthma. METHODS: One hundred and thirty-six nonsmoking asthmatic adults with persistent symptoms despite high doses of inhaled or oral corticosteroids and long-acting bronchodilators were studied [70% female, median (range) age 44.6 (18-75) years, 32% on daily oral corticosteroids]. The association between obesity, lung function parameters [forced expiratory volume in 1 s (FEV(1)), functional residual capacity/total lung capacity (FRC/TLC)], inflammatory markers [blood eosinophils, sputum eosinophils and neutrophils, exhaled nitric oxide (FE(NO)), airway hyperresponsiveness, C-reactive protein (CRP)] and aggravating co-morbid factors (severe chronic sinus disease, gastro-esophageal reflux, recurrent respiratory infections, psychopathology and obstructive sleep apnea) was investigated. RESULTS: Obese patients (n = 29) had a higher FEV(1)%pred (P = 0.05) and a lower FRC/TLC%pred (P < 0.01) compared with nonobese patients (n = 107). Body mass index was inversely related with sputum eosinophils (r = -0.36, P < 0.01) and FE(NO) (r = -0.30, P < 0.01). Obese patients had an increased risk for gastro-esophageal reflux (OR = 2.3) and sleep apnea (OR = 3.1). CONCLUSION: Obesity in patients with difficult-to-treat asthma is inversely related with sputum eosinophils and FE(NO), and positively associated with the presence of co-morbid factors and reduced lung volumes. This suggests that other factors than airway inflammation alone explain the relationship between obesity and asthma severity.

Iron deficiency in the first 6 months of age in infants born between 32 and 37 weeks of gestational age.

BACKGROUND/OBJECTIVES: Preterm infants are at risk of iron deficiency (ID). In the Netherlands, preterm infants born after 32 weeks of gestational age (GA) do not receive iron supplementation on a routine basis. We hypothesized that dietary iron intake in these infants might not be sufficient to meet the high iron requirements during the first 6 months of life. SUBJECTS/METHODS: In a prospective cohort study, we analyzed the prevalence and risk factors of ID in 143 infants born between 32+0 and 36+6 weeks GA who did not receive iron supplementation. RESULTS: ID at the age of 4 and 6 months was present in 27 (18.9%) and 7 (4.9%) infants. Results of a multivariable logistic regression analysis showed that ID was associated with lower birth weight, a shorter duration of formula feeding, more weight gain in the first 6 months of life and lower ferritin concentrations at the age of 1 week. CONCLUSIONS: Preterm infants born after 32 weeks GA have an increased risk of ID compared with those born at term, supporting the need of iron supplementation. Our results suggests that measurement of ferritin at the age of 1 week might be useful to identify those infants at particular risk and could be used in populations without general supplementation programs. However, the efficacy and safety of individualized iron supplementation, based on ferritin concentrations at the age of 1 week, together with other predictors of ID, needs to be further investigated, preferably in a randomized controlled trial.

Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma.

Alveolar nitric oxide (NO) is a measure of peripheral airway inflammation in asthma, potentially associated with disease severity. The relationship between alveolar NO and physiological tests of peripheral airway (dys)function has not been investigated. The present authors hypothesised that peripheral airway inflammation and dysfunction are inter-related and associated with asthma severity. Alveolar NO was compared between 17 patients with mild-to-moderate asthma and 14 patients with severe asthma and related to total lung capacity (TLC), residual volume (RV)/TLC, thoracic gas volume (FRC), slope of the single breath nitrogen washout curve (dN2), closing capacity (CC)/TLC and fall in forced vital capacity at the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second. In patients with severe asthma, strong correlations were found between alveolar NO and RV/TLC % pred, FRC % pred, dN2, and CC/TLC. Patients with oral steroid-dependent asthma had higher alveolar NO levels (2.7 ppb) compared with the other patients with severe (0.6 ppb) and mild-to-moderate asthma (0.3 ppb). The present authors conclude that alveolar nitric oxide is closely related to parameters of peripheral airway dysfunction in patients with severe asthma, and that oral steroid-dependent asthmatics have more peripheral airway disease than nonsteroid-dependent asthmatics. This suggests that patients on chronic oral steroid treatment have more extensive disease and require additional anti-inflammatory treatment to better target the peripheral airways.

Unstable pelvic fractures: a retrospective analysis.

Thirty-nine patients with unstable pelvic fractures were analysed retrospectively. The mean age of the group was 41 years (range 15-77). Of these cases 35 had sustained high energy trauma. The mean Hospital Trauma Index-Injury Severity Score of the population was 32 (16-66). Nine cases were haemodynamically unstable on admission. The type of unstable pelvic fracture was classified according to Tile. Sixteen patients had a type B fracture and 23 had a vertical instability (type C) fracture. In two patients, an open fracture was seen. Directly associated injuries were diagnosed in 11 patients, of which eight showed damage of the urogenital system, three of the rectum and three of the peripheral nerve system. In seven cases the fracture was treated non-operatively; in the remaining 32 patients the pelvic ring was stabilized operatively. Additional therapy for hypovolaemic shock due to pelvic bleeding was necessary in six cases. The overall mortality in this series was 13 per cent. Early and aggressive resuscitation and standardized treatment in well-equipped and staffed injury centres is mandatory in these severely traumatized patients to achieve optimal results and to minimize the risk of fatal outcome.

Cloning and characterization of human liver cytosolic beta-glycosidase.

Cytosolic beta-glucosidase (EC 3.2.1.21) from mammalian liver is a member of the family 1 glycoside hydrolases and is known for its ability to hydrolyse a range of beta-D-glycosides, including beta-D-glucoside and beta-D-galactoside. We therefore refer to this enzyme as cytosolic beta-glycosidase. We cloned the cDNA encoding the human cytosolic beta-glycosidase by performing PCR on cDNA prepared from total human liver RNA. Specific primers were based on human expressed sequence tags found in the expressed sequence tag database. The cloned cDNA contained 1407 nt with an open reading frame encoding 469 amino acid residues. Amino acid sequence analysis indicates that human cytosolic beta-glycosidase is most closely related to lactase phlorizin hydrolase and klotho protein. The enzyme was characterized by using cell lysates of COS-7 cells transfected with a eukaryotic expression vector containing the cDNA. The biochemical, kinetic and inhibition properties of the cloned enzyme were found to be identical with those reported for the enzyme purified from human liver.