Inhaled corticosteroids do not affect the antibody titer against the SARS-CoV-2 spike protein in BNT162b2 mRNA vaccinated patients.

OBJECTIVES: Oral corticosteroids reduce the antibody titer of the BNT162b2 mRNA vaccine against SARS-CoV-2. To date, the effect of inhaled corticosteroids on antibody titers is unknown. STUDY DESIGN: The design of this study is retrospective study. METHODS: We analyzed the relationship between the clinical features and total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in 320 subjects who had never been infected with Coronavirus disease 2019 (COVID-19) and were vaccinated the second time with the BNT162b2 mRNA vaccine between October 1 to December 28, 2021. RESULTS: Of the 320 subjects, 205 were treated with inhaled corticosteroids. The median antibody titer of patients treated with inhaled corticosteroids was 572 U/mL, which was significantly higher than that of patients treated without inhaled corticosteroids (454U/mL, P = 0.00258). The median antibody titers of smokers, men, and patients aged 65 years and over, were 315.5 U/mL, 385 U/mL, and 425.5 U/mL, respectively. These results are significantly lower than those of patients who never smoked, women, and patients aged less than 64 years (582 U/mL [P < 0.0001], 682.5 U/mL [P < 0.0001], and 717 U/mL [P < 0.0001], respectively). The multivariate analysis revealed that females and age were independent antibody titer-reducing factors (P = 0.0001 and P < 0.0001, respectively). CONCLUSIONS: The use of inhaled corticosteroids did not reduce the antibody titer against SARS-CoV-2 spike protein. Clinicians should continue treatment with inhaled corticosteroids if indicated.

Retrospective Analysis of the Starting Dose of Combined ICS/LABA for Cough-variant Asthma and Cough-predominant Asthma.

BACKGROUND/AIM: Although the usefulness of inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) in cough-variant asthma and cough-predominant asthma has been reported, there is no consensus on its starting dose. The aim of this study is to find the optimal dose of ICS/LABA for cough-variant asthma and cough-predominant asthma. PATIENTS AND METHODS: We analysed 112 patients who visited our clinic from January 2009 to December 2012 with the chief complaint of cough that had continued for more than 3 weeks. Cough-variant asthma (n=30) and cough-predominant asthma (n=7) were treated with ICS/LABA. RESULTS: There was no significant difference in cough duration time from starting ICS/LABA in cough-variant asthma and cough-predominant asthma between medium and high doses (14.3% versus 10.9%, respectively) (p=0.192). Moreover, there was no significant difference in cough duration time from starting ICS/LABA in cough-variant asthma between medium and high doses (13.2% versus 11.5%, respectively) (p=0.433). CONCLUSION: The medium starting dose of ICS/LABA is sufficient for treating cough-variant asthma.

Usefulness Analysis of Fraction of Exhaled Nitric Oxide for the Differential Diagnosis of Acute Cough.

BACKGROUND/AIM: Measuring the fraction of exhaled nitric oxide (FeNO) is useful in the diagnosis of asthma and cough variant asthma. The aim of this study was to clarify the significance of measuring the FeNO in the differential diagnosis of acute cough. PATIENTS AND METHODS: We analyzed 80 patients who visited the clinic with the chief complaint of acute cough having experienced an asthma-like episode from January 2014 to July 2015. RESULTS: Infectious cough alone was present in 21% of patients, while 30% had asthmatic cough alone and 49% had a combination of infectious and asthmatic cough. The values of FeNO in those with asthmatic cough (30.4±24.7 ppb) and asthmatic/infectious cough (33.2±17.4 ppb) were significantly higher than those with just infectious cough (13.7±3.2 ppb) (p=0.0089 and p<0.0001, respectively). CONCLUSION: FeNO measurement is useful for distinguishing asthmatic diseases, even in the differential diagnosis of acute cough.

Retrospective Study of the Effects of Post-nasal Drip Symptoms on Cough Duration.

BACKGROUND/AIM: The aim of this study was to elucidate the significance of allergic rhinitis and post-nasal drip symptoms in patients with cough-variant and cough-predominant asthma. PATIENTS AND METHODS: We conducted a retrospective analysis of 91 patients who had cough-variant or cough-predominant asthma and first visited the Nakajima Medical Clinic in Japan between June 2012 and July 2015. RESULTS: Post-nasal drip symptoms were reported in 58 (63.7%) patients. The patients with post-nasal drip symptoms (19.5±8.3 days) had a significantly longer time until cough disappearance than those without post-nasal drip symptoms (11.0±4.8 days) (p=0.000034). Multivariate analysis showed that post-nasal drip symptoms are independent prolonged factors of cough duration. CONCLUSION: Post-nasal drip symptoms may affect cough control in patients with cough-variant and cough-predominant asthma.

Retrospective analysis of the effect of inhaler education on improvements in inhaler usage.

INTRODUCTION: Various types of inhalation devices have been released, and it is necessary to acquire the skills for using each of them. The factors that have been previously associated with poor inhalator usage include gender, duration of disease, age, and the type of device. However, it is unclear whether these factors also apply to the Japanese population. The number of education sessions needed to acquire inhaler usage skills is also not established. PATIENTS AND METHODS: We performed a retrospective review of the medical records of selected patients and their subjective assessments of their inhaler usage skills between January 2016 and March 2018. The primary outcome was the effect of inhaler education for each inhaler device. The secondary outcomes were the factors affecting the effectiveness of inhaler education, the effects of inhalation education stratified by age, and the number of inhaler education sessions needed to improve inhaler usage skills. RESULTS: Data from 399 patients were analyzed. Age and the type of delivery device affected the mastery of inhaler usage skills. Approximately half of the patients had acquired inhaler usage skills during baseline evaluation. Approximately 90% of patients acquired inhalation usage skills after two education sessions, regardless of the type of inhalation device. Among the older patients, 35.0% had acquired inhaler usage skills during the baseline evaluation, and 86.8% acquired them after two education sessions. CONCLUSIONS: Inhaler usage skills significantly improved, regardless of the device, after inhalation education, and this was also observed in elderly patients after two education sessions.

An Investigation on the Consciousness of Patients and Pharmacists Regarding Inhaler Education.

Few studies have focused on the awareness of inhaler education in patients and pharmacists who have crucial roles in inhaler education. The aim of this study was to investigate the difference in awareness of inhaler education between patients and pharmacists. We conducted questionnaire-based surveys involving 270 patients with asthma and chronic obstructive pulmonary disease and 139 pharmacists of 13 pharmacies belonging to the same chain dispensing pharmacy in Hyogo prefecture of Japan in July 2011. We obtained valid responses from 230 patients (85.2%) and 139 pharmacists (100%). Although 75% of pharmacists provided inhaler education about the importance of continuation, only 16% of patients felt that they had learned the importance of continuation. Similarly, 95% of pharmacists provided inhaler education about the importance of gargling, however, only 57% of patients felt that they had learned the importance of gargling. This survey clarified the difference in awareness between pharmacists and patients on inhaler education. It proved to be difficult to educate patients on the importance of compliance and gargling.

A Questionnaire Survey of the Inhalation Instruction in Pharmacies.

Few studies have focused on the inhalation instruction in pharmacies which have the crucial role on the inhalation instruction. The aim of this study is to evaluate the level of knowledge and the degree of interest for asthma inhalation instruction methods among pharmacists receiving prescription from clinics. We conducted questionnaire surveys to chief pharmacists of 39 consecutive pharmacies belonging to HANSHIN Dispensing Pharmacy in Hyogo, Japan at July 2011. We obtained valid responses from 35 pharmacies. Among them, 14 pharmacies dealt with prescriptions mainly from the clinics (clinic pharmacies) and 21 pharmacies dealt with prescriptions originated from hospitals (hospital pharmacies), including 13 pharmacies that dealt with prescription filled by respiratory physicians (specialty hospital pharmacies). Although the inhalation instruction at the first visit was provided at every pharmacy, only 54.3% of all pharmacies provided inhalation instructions after the second visit. Compared to 0% of the clinic pharmacies, 40% of the specialty hospital pharmacies visually checked the patient's inhalation procedure after the second visit. Visual confirmation of the inhalation technique, especially in the clinic pharmacies, might play an important role in maintaining treatment adherence.

A Cross-sectional Survey of the Clinical Manifestations and Underlying Illness of Cough.

AIM: The aim of this study was to identify factors affecting the final diagnosis of cough. MATERIALS AND METHODS: This study recruited 463 consecutive patients who visited five Japanese general hospitals due to cough from October 2006 to September 2007. Of these, 418 patients (90%) who completed a questionnaire designed to acquire data regarding clinical manifestations of cough were included. RESULTS: Most patients with bronchial asthma had cough with seasonal variation and wheezing. Patients with gastro esophageal reflux disease suffered from heartburn and cough without daily or seasonal variation. Cough associated with sinobronchial syndrome was only observed in females and was linked to increased sputum. Patients with whooping cough were bothered by cough interrupting sleep and talking. Patients with cardiogenic cough had exertional dyspnea. CONCLUSION: The specific items on our questionnaire relating to patient characteristics, complications, and triggers of cough, represent useful tools for diagnosing the primary disease producing cough.

An Open-Label, Multi-Institutional, Randomized Study to Evaluate the Additive Effect of a Leukotriene Receptor Antagonist on Cough Score in Patients with Cough-Variant Asthma Being Treated with Inhaled Corticosteroids.

Cough-variant asthma is one of the most common reasons for chronic cough. It is important to treat appropriately cough-variant asthma because 30% to 40% of cough-variant asthma becomes a typical asthma. However, little is known about the treatment of cough-variant asthma except for inhaled corticosteroid (ICS). The aim of this study was to validate the additive efficacy of a leukotriene receptor antagonist (LTRA) on cough score and respiratory function in patients with cough-variant asthma being treated with ICS. A total 28 patients were randomly assigned to either an ICS + LTRA group or an ICS group. There were statistically significant improvements in cough scores in the ICS + LTRA group from 0 weeks (6.7 ± 4.4) to 2 weeks (2.9 ± 3.2) (P < 0.05), 4 weeks (0.7 ± 1.1) (P < 0.001), and 8 weeks (0.8 ± 1.2) (P < 0.001). However similar improvements were not evident in the ICS group from 0 weeks (6.7 ± 4.4) to 2 weeks (5.6 ± 10.0) (P = 0.59), 4 weeks (4.6 ± 7.6) (P = 0.32), and 8 weeks (2.9 ± 5.2) (P = 0.08). On the other hand, no significant changes were evident in the forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC). In conclusion, the LTRA was useful in improving cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.

Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1.

Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.

A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica.

LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. LHX4/Lhx4 is a protein that is essential for pituitary development and motor neuron specification in mammals. In human, a heterozygous splicing mutation of the LHX4 gene was reported in a family with combined pituitary hormone deficiencies (CPHD). In addition to CPHD, these patients were characterized by small sella turcica and chiari malformation. Here we report a Japanese patient with CPHD (GH, PRL, TSH, LH, FSH, and ACTH deficiency) due to a novel missense mutation (P366T) of the LHX 4 gene. She showed severe respiratory disease and hypoglycemia soon after birth. Brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and chiari malformation. Sequence analysis of the LHX 4 gene identified a heterozygous missense mutation (P366T) in exon 6, which was present in LIM4 specific domain. Neither of the patient's parents harbored this mutation, indicating de novo mutation.

Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation.

BACKGROUND: Cough variant asthma has recently been described, mainly as airway inflammation in relation to bronchial asthma, but the relationship between the two types of asthma remains unclear. Further studies of cough receptor sensitivity are necessary to fully characterize cough variant asthma. METHODS: We assessed the relevance of testing cough sensitivity using an Astograph with continuous capsaicin inhalation, and compared the results with those obtained using intermittent inhalation. We showed the clinical applicability of testing cough sensitivity (0.156-80 microM capsaicin; five or more coughs, 1 minute of continuous inhalation at each concentration) using this method. We compared cough sensitivity among patients with pure cough variant asthma who did not develop bronchial asthma after an observation period of at least 1 year, patients with bronchial asthma and healthy individuals. RESULTS: The continuous cough sensitivity test using the Astograph was reproducible and reliable. Cough sensitivity in patients with pure cough variant asthma was significantly higher than that in healthy individuals. CONCLUSIONS: The cough sensitivity of patients with cough variant asthma is not necessarily identical to that of healthy individuals.

Characteristics of patients with chronic cough who developed classic asthma during the course of cough variant asthma: a longitudinal study.

BACKGROUND: Some patients develop asthmatic symptoms such as wheezing and dyspnea during the course of cough variant asthma (CVA), which are considered precursors of classical asthma. OBJECTIVES: To identify the characteristics of such patients, we investigated the nature of CVA patients with or without developing bronchial asthma in the longitudinal study. METHODS: In 28 CVA patients whom we could observe over 5 years, duration of coughing, physical examination findings, pulmonary function and bronchial hyperresponsiveness to inhaled methacholine were retrospectively assessed. RESULTS: Of these patients with CVA, 10 developed the asthmatic symptoms of wheezing and dyspnea (precursors of classical asthma) over 5 years. All these 10 patients showed marked bronchial hyperresponsiveness; however, there were no significant differences in the bronchial responsiveness to methacholine between patients with precursors of classical asthma and pure CVA patients who did not wheeze. The duration of coughing had a significant relationship with precursors of classical asthma. Seven patients with precursors of classical asthma developed wheezing in the first year and 1 patient each in the second, third and fourth year. CONCLUSIONS: These findings of a 5-year observation suggest that longer duration of coughing may be an important factor that develops precursors of classical asthma in patients with CVA.

Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient.

HESX1/Hesx1 is a member of the paired-like class of homeobox genes and is essential for pituitary and forebrain development. Mice with a targeted homozygous deletion of the Hesx1 show severe central nervous system defects, absence of optic vesicles, and a very small anterior pituitary gland. This phenotype is similar to the abnormalities observed in the human disorder called septo-optic dysplasia, a syndromic form of congenital hypopituitarism. To date, four missense mutations in the human HESX1 have been described in individuals with phenotypes ranging from severe septo-optic dysplasia, relatively mild combined pituitary hormone deficiency (CPHD), to isolated GH deficiency. Here we report a Japanese patient with CPHD (GH, TSH, LH, FSH, and ACTH deficiency) due to a novel sporadic HESX1 mutation. Brain magnetic resonance imaging examination revealed hypoplastic anterior pituitary, ectopic posterior lobe, and left optic nerve hypoplasia. Molecular analysis identified the insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. This mutation changes a reading frame and introduces a premature stop codon soon after the mutation site. Therefore, this mutation would be predicted to generate a protein lacking the carboxyl-terminal homebox domain (DNA-binding domain) and cause the disease. Family analysis demonstrated that neither of the patient's parents harbored this mutation, indicating that the mutation had arisen de novo. In conclusion, a de novo heterozygous frameshift mutation in exon 2 of the HESX1 causes severe CPHD with optic nerve hypoplasia in a human.