Spirometry-Adjusted Fraction of Exhaled Nitric Oxide Allows Asthma Diagnosis in Children, Adolescents, and Young Adults.

BACKGROUND: Recently, it has been proved that fractional exhaled nitric oxide (FENO) results are in disagreement with other measurements of asthma control. The objective of this work is to present and validate new lung function/lung inflammation ratios. METHODS: This is a retrospective, cross-sectional study in which we evaluated data from medical documentation of 1,529 pediatric and adolescent subjects and a small number (2% of the studied population) of young adults, who presented symptoms suggestive of asthma (age range 4-24 y). We are the first to analyze results obtained in this manner (before the introduction of controlled medication): FENO, spirometry, specific resistance of the airways, diagnosis of allergic diseases, and allergen sensitization (specific immunoglobulin E results). RESULTS: Cut-off points for the new indicators allowed us to diagnose asthma in the study participants: for FVC/FENO ratio, 0.17 L/ppb; for FEV1/FENO ratio, 0.15 L/ppb; for forced expiratory flow during the middle half of the FVC maneuver (FEF25-75%)/FENO ratio, 0.16 L/s/ppb; for FENO/FVC ratio, 11.00 ppb/L; for FENO/FEV1 ratio, 12.53 ppb/L; and for FENO/FEF25-75% ratio, 11.81 ppb/L/s. Only the ratios described above were closely correlated with the diagnosis of asthma and with one another. They significantly differed between subjects with asthma and healthy subjects as well as between females and males. Only FEF25-75%/FENO and FENO/FEF25-75% values were significant predictors of any sensitization in the studied subjects. We found higher sensitivity than specificity and higher positive predictive value than negative predictive value for FVC/FENO, FEV1/FENO, and FEF25-75%/FENO and found a mirror image for reverse parameters. However, the positive predictive values and negative predictive values were not clearly convincing with respect to diagnostic accuracy in the case of the new parameters proposed. CONCLUSIONS: We propose new lung function/lung inflammation ratios by which it may become possible to diagnose asthma in children and adolescents on the basis of a subject's spirometry and FENO measurements. We believe that our ratios are only supportive of the universally used parameters in the process of diagnosing asthma. (ClinicalTrials.gov registration NCT01805635.).

The interpretation of exhaled nitric oxide values in children with asthma depends on the degree of bronchoconstriction and the levels of asthma severity.

BACKGROUND: The clinical implications of fractional exhaled nitric oxide (F(ENO)) measurements in childhood asthma are unclear. We aimed to evaluate the relationship between the level of exhaled nitric oxide and pre-bronchodilator FEV1 and the change in FEV1 after bronchodilator in children with asthma. METHODS: This was a retrospective, cross-sectional study. We evaluated data from medical documentation of children with asthma with special attention to F(ENO) results, asthma severity, FEV1 (% predicted), and bronchial reversibility test. RESULTS: Four hundred and five subjects (age 6-18 y) completed the study. Median levels of F(ENO) increased linearly with subjects' age (P = .03). We found a nonlinear trend of pre-bronchodilator FEV1 across 4 quartiles of F(ENO) in episodic and mild asthma; we observed lower pre-bronchodilator FEV1 in children with higher F(ENO), but only up to the F(ENO) value of 35.4 ppb; in children with F(ENO) value > 35.4 ppb, pre-bronchodilator FEV1 was increased. We found a linear increasing trend of change from baseline (after 400 µg of salbutamol) in FEV1 across F(ENO) categories in children with moderate asthma. CONCLUSIONS: Our results suggest a need to measure F(ENO) before as well as after spirometry. Consequently, in children with asthma with bronchial obstruction, we suggest assessing F(ENO) after short-acting ß2 agonists as well. (ClinicalTrials.gov registration NCT00815984.).

Diagnostic value of lung function parameters and FeNO for asthma in schoolchildren in large, real-life population.

BACKGROUND AND OBJECTIVE: To establish a diagnostic value of fractional exhaled nitric oxide (FeNO), interrupter resistance measurement (Rint), specific resistance of the airways (sRaw), spirometric parameters in asthma diagnosis in schoolchildren. METHODS: It was a retrospective, cross-sectional study. We evaluated data from medical documentation of 6,439 children (aged 6-18) with symptoms suggestive of asthma, who attended our Pediatric Allergic Outpatient Clinic. Medical documentation of the patients was analyzed with special attention to the first ever obtained results (before the introduction of controller medication) of: FeNO, Rint, sRaw, spirometry, diagnoses of allergic diseases, and allergen sensitization (specific IgE results). RESULTS: We included 3,612 children in the analysis. Older age, male gender, the presence of allergic rhinitis, sensitization to perennial and seasonal allergens, higher FeNO and Rint, and FEV1 /FVC <80% were significantly associated with asthma. We observed a significant association between FeNO and Rint in the prediction of asthma diagnosis. Optimal cutoff points to differentiate asthmatics from non-asthmatics were established. Thus, Rint >175.4% was defined as asthma-predicting Rint, and FeNO >15.8 ppb was defined as asthma-predicting FeNO. In all study subgroups, sensitivity for asthma-predicting Rint was significantly higher than for asthma-predicting FeNO with an inverse trend in specificity value. CONCLUSION: Our results suggest that asthma-predicting Rint and, to a lesser extent, asthma-predicting FeNO, defined in the present study, could serve as a reliable tool to exclude asthma in schoolchildren. However, our results also indicate a clinically important fact that all lung function parameters or FeNO should be interpreted in the context of age, gender, allergy profile, and the presence of co-morbidities in schoolchildren. Pediatr Pulmonol. 2014; 49:632-640. © 2013 Wiley Periodicals, Inc.

Cloning and expression of a new recombinant thrombolytic and anthithrombotic agent - a staphylokinase variant.

To develop a more potent antithrombin agent with thrombolytic and antiplatelet properties, a new staphylokinase (SAK) variant was constructed. The kringle 2 domain (K2) of tissue type-plasminogen activator (t-PA) containing a fibrin-specific binding site (i), the RGD sequence (Arg-Gly-Asp) for the prevention of platelet aggregation (ii) and the antithrombotic agent - hirulog (iii) was assembled to the C-terminal part of recombinant staphylokinase (r-SAK). cDNA for the hybrid protein SAK-RGD-K2-Hirul was cloned into Pichia pastoris pPIC9K yeast expression vector. The introduction of K2 t-PA, the RGD sequence and hirulog into the C-terminus of r-SAK did not alter the staphylokinase activity. We observed a higher clot lysis potency of SAK-RGD-K2-Hirul as evidenced by a faster and more profound lysis of (125)I-labeled human fibrin clots. The potency of thrombin inhibition by the hirulog C-terminal part of the recombinant fusion protein was almost identical to that of r-Hir alone. These results suggest that the SAK-RGD-K2-Hirul construct can be a more potent and faster-acting thrombolytic agent with better antithrombin and antiplatelet properties compared to r-SAK and SAK-RGD-K2-Hir.