Shizuoka Prefectural Hospital Organization

Despite the development of biologics for severe asthma, individuals with uncontrolled status persist, posing a significant social problem. This multicenter prospective study aimed to identify factors associated with the uncontrolled status of patients with severe asthma in the biologic era assessed using the Asthma Control Questionnaire (ACQ).

Subjects with severe asthma diagnosed by respiratory specialists were enrolled from 11 hospitals. Clinical data and questionnaires were collected. We compared controlled (ACQ-5 <1.5) with uncontrolled severe asthma (ACQ-5 ≥1.5) and assessed factors linked to uncontrolled severe asthma using logistic regression analysis.

One hundred fifty-four patients were analyzed (median age, 66 years; 62.3 % female; 52.6 % administered biologics). Among them, 56 patients (36.4 %) had uncontrolled severe asthma (ACQ-5 ≥1.5). The uncontrolled group had more frequent exacerbations (≥2 times in the previous year) and elevated blood neutrophil counts compared with the controlled group. Factors associated with uncontrolled status were analyzed in the overall population, with patients stratified into two groups: those receiving biologics and those not receiving biologics. Multivariate analysis revealed that frequent exacerbations and elevated blood neutrophil counts were associated with uncontrolled status in the overall population and in patients without biologics, whereas elevated blood neutrophil counts were significantly associated with uncontrolled status in patients receiving biologics.

Elevated blood neutrophil counts and frequent exacerbations were independently associated with uncontrolled severe asthma. Specifically, elevated blood neutrophil counts were a significant factor related to uncontrolled status irrespective of biologics, suggesting their potential utility as a biomarker in the biologic era.

Subacute cough is subdivided and distinguished from chronic cough, because post-infectious cough is considered to be the main cause of subacute cough and differs from acute and chronic cough. However, the details of the spectrum and frequency of causes of subacute cough remain unclear because only two studies on subacute cough have been published.

Patients who presented with cough that lasted for 3-8 weeks and visited respiratory clinics or hospitals affiliated with the Japan Cough Society during 2 years were studied.

A total of 148 patients were prospectively enrolled, and those who did not meet the definition of subacute cough were excluded. Ninety-seven (68.3%) patients with subacute cough progressed to chronic cough, and the main causative diseases were cough variant asthma in 44 patients, atopic cough in 24 patients, sinobronchial syndrome in 13 patients, and post-infectious cough in seven patients. Patients with cough variant asthma complicated by atopic cough and those in whom the cause of subacute cough was unknown tended to develop chronic cough.

This study shows that post-infectious cough is less common than previously thought and the main causes of subacute cough are cough variant asthma, atopic cough, and sinobronchial syndrome and their complications. Cough variant asthma in combination with atopic cough also can be a precursor of refractory chronic cough. The careful diagnosis and treatment of two or more causative diseases is required in patients with subacute cough.

Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity.

CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination.

Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V_max inhibition [V_{max, inh}] = 100 %; V_max = 0). The estimated parameters of V_max,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher.

CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V_max,inh of voriconazole in children with malignancy or inborn errors of immunity.