Blood eosinophil count and FeNO to predict benralizumab effectiveness in real-life severe asthma patients.

OBJECTIVE: Benralizumab is a promising drug for severe uncontrolled asthma. This study aimed to clarify the effectiveness of benralizumab in a real-life setting. METHODS: Subjects included 24 patients with severe type 2 asthma who received benralizumab between April 2018 and July 2019. Changes in parameters, exacerbation frequency, and oral corticosteroid (OCS) use after 4 and 24 weeks of administration were examined. The parameters included the Global Evaluation of Treatment Effectiveness (GETE) scale, Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), blood eosinophils, fractional exhaled nitric oxide (FeNO), and spirometry. The response to treatment was defined as follows: for patients with exacerbations or OCS use before treatment initiation, a reduction of ≥50% in exacerbation frequency or OCS use; and for patients without exacerbations or OCS use, an improvement of ≥0.5 in ACQ scores and ≥3 in ACT scores, or of ≥10.38% in FEV1. RESULTS: Twenty-one patients completed the treatment for 24 weeks. Excellent and good GETE scales and ACQ and ACT improvement were found in 67% of the patients at 4 weeks, and the effect continued until 24 weeks. The patients' rate with exacerbations was significantly reduced compared to the previous 24 weeks before administration. In 17 patients receiving OCS, the use could be reduced or quit in 14 patients. Overall, 16 patients (76.2%) met the responder definition and could be predicted by the baseline eosinophil count and FeNO levels with the best cutoff values of 100/µL and 40 ppb, respectively. CONCLUSIONS: Blood eosinophil and FeNO could predict benralizumab effectiveness.

Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice.

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing.IMPORTANCE The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.

Effectiveness of a 23-valent pneumococcal polysaccharide vaccine for the prevention of pneumococcal pneumonia in the elderly with chronic respiratory diseases: a case-control study of a single center.

BACKGROUND: The effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in preventing pneumococcal pneumonia has been controversial. METHODS: To evaluate the effectiveness of the PPSV23 in elderly outpatients with chronic respiratory diseases, we carried out a case-control study, including 4128 outpatients aged ≥ 65 years, in the respiratory department. RESULTS: There were 320 vaccinated patients, of which 164 were diagnosed with pneumococcal pneumonia. The adjusted odds ratio was 0.39 (95% confidence interval (CI), 0.17 to 0.89). In the subsets consisting of age groups ≥ 70 and ≥ 75 years, the adjusted odds ratio (95% CI) was respectively 0.16 (0.04 to 0.67) and 0.15 (0.02 to 1.12). CONCLUSION: This real-world study suggests that PPSV23 can be useful in preventing pneumococcal pneumonia in the elderly with chronic respiratory diseases.

Modulation of gut microbiota composition due to early weaning stress induces depressive behavior during the juvenile period in mice.

BACKGROUND: The gut microbiota plays an important role in the development of behavior and immunity in infants and juveniles. Early weaning (EW), a form of social stress in mice, leads to increased anxiety and an enhanced stress response in the hypothalamic-pituitary-adrenal axis during adulthood. Early life stress also modulates the immune system and increases vulnerability to infection. However, studies investigating the causal relationships among juvenile stress, microbiota changes, and immune and behavioral deficits are limited. Therefore, we hypothesized that EW alters gut microbiota composition and impairs the development of the nervous and immune systems. RESULTS: EW mice moved longer distances in the marble-burying test and had longer immobility times in the tail suspension test than normal weaning (NW) mice. In parallel, the gut microbiome composition differed between NW and EW mice, and the abundance of Erysipelotrichacea in EW mice at 8 weeks of age was lower than that in NW mice. In an empirical study, germ-free mice colonized with the gut microbiota of EW mice (GF-EW mice) demonstrated higher depressive behavior than GF mice colonized with normal weaning microbiota (GF-NW mice). Immune cell profiles were also affected by the EW microbiota colonization; the number of CD4 + T cells in the spleen was reduced in GF-EW mice. CONCLUSION: Our results suggest that EW-induced alterations in the gut microbiota cause depressive behaviors and modulate the immune system.

Intergenerational transmission of maternal behavioral traits in mice: involvement of the gut microbiota.

The matrilineal transmission of maternal behavior has been reported in several species. Studies, primarily on rats, have suggested the importance of postnatal experience and the involvement of epigenetic mechanisms in mediating these transmissions. This study aims to determine whether the matrilineal transmission of maternal behavior occurs in mice and whether the microbiota is involved. We first observed that early weaned (EW) female mice showed lower levels of maternal behavior, particularly licking/grooming (LG) of their own pups, than normally weaned (NW) female mice. This difference in maternal behavioral traits was also observed in the second generation, even though all mice were weaned normally. In the subsequent cross-fostering experiment, the levels of LG were influenced by the nurturing mother but not the biological mother. Finally, we transplanted the fecal microbiota from EW or NW mice into germ-free (GF) mice raising pups. The maternal behaviors that the pups exhibited toward their own offspring after growth were analyzed, and the levels of LG in GF mice colonized with microbiota from EW mice were lower than those in GF mice colonized with microbiota from NW mice. These results clearly indicate that, among maternal behavioral traits, LG is intergenerationally transmitted in mice and suggest that the vertical transmission of microbiota is involved in this process. This study demonstrates the universality of the intergenerational transmission of maternal behavioral traits and provides new insights into the role of microbiota.

Mucus Plugs and Small Airway Dysfunction in Asthma, COPD, and Asthma-COPD Overlap.

PURPOSE: There are reports concerning mucus plugs detected on high-resolution computed tomography images and airflow obstruction in asthma and chronic obstructive pulmonary disease (COPD). However, little is known about the associations between mucus plugs and small airway dysfunction (SAD). We evaluated the relationship between mucus plugs and pulmonary function in patients with asthma, COPD, and asthma-COPD overlap (ACO), and investigated the relevance to SAD and type 2 inflammation in a retrospective study. METHODS: Subjects included 49 asthmatic, 40 ACO, and 41 COPD patients. ACO was diagnosed based on the Japanese Respiratory Society ACO guidelines. Clinical and laboratory parameters, including blood eosinophil count, serum total IgE levels, fractional exhaled nitric oxide (FeNO), spirometry, and forced oscillation technique (FOT), were compared between patients with and without mucus plugs. RESULTS: Mucus plugs were found in 29 (59%) asthmatic, 25 (65%) ACO, 17 (41%) COPD patients. Patients with mucus plugs had reduced spirometry and larger FOT parameters, especially in COPD patients. Mucus scores correlated positively with IgE in ACO and FeNO in asthmatic patients, but not in COPD patients. Multivariate logistic regression analysis revealed that SAD parameters, including forced vital capacity and resonant frequency, a respiratory reactance parameter, were significantly associated with the presence of mucus plugs in the whole studied population. CONCLUSIONS: SAD, rather than large airway dysfunction, was associated with mucus plugs in asthma, ACO, and COPD patients.

TAK - 021, an inactivated Enterovirus 71 vaccine candidate, provides cross-protection against heterologous sub-genogroups in human scavenger receptor B2 transgenic mice.

BACKGROUND: Enterovirus 71 (EV71) is a major cause of outbreaks of hand, foot and mouth disease, most frequently in children, and is a public health concern in the Asia-Pacific region. Takeda is developing TAK-021, an inactivated EV71 vaccine candidate based on sub-genogroup B2 strain MS87. In a phase I clinical trial, TAK-021 was safe, well tolerated, and immunogenic in healthy adults and elicited cross-neutralizing antibodies against heterologous EV71 sub-genogroup viruses. TAK-021 confers protection from lethal challenge with a mouse-adapted homologous strain in AG129 mice. However, it has not been determined whether TAK-021 can provide cross-protection against heterologous EV71 sub-genogroups. METHODS: We examined the efficacy of TAK-021 against challenge with EV71 sub-genogroups B4, B5, C1, C2, and C4 on day 42 (short-term) and sub-genogroups B5 and C4 on day 120 (long-term) after immunization of human scavenger receptor B2 transgenic (hSCARB2-tg) mice with TAK-021 on days 0 and 28. Antibody titers were monitored over 120 days using plaque reduction neutralization test of the homologous vaccine virus. RESULTS: TAK-021 elicited neutralizing antibody (nAb) in greater than 90% of the mice and nAb persisted through day 120. Challenge of control animals led to weight loss and death, as well as virus detection in various organs and histopathological lesions in the brain. All mice that received two doses of TAK-021 developed nAb and survived a short-term challenge given on day 42, while more than 80% survived a long-term challenge given on day 120. EV71 was detected less frequently and at lower levels in organs of immunized mice compared to non-immunized control mice. CONCLUSIONS: The results show that TAK-021 can confer protection in mice against the EV71 sub-genogroups tested.

Laryngomalacia presenting as severe uncontrolled asthma.

Congenital laryngomalacia is the most common cause of stridor in infants and usually resolves without therapy by 12-18 months of age. However, a recent study found that laryngomalacia may leave structural and functional traces with increased risk of later respiratory symptoms, suggesting that late-onset laryngomalacia may represent long-term consequences of milder or even undiagnosed forms. Unusual cases demonstrated that inspiratory stridor developed subsequent to upper respiratory tract infections. The lack of airway hyperresponsiveness in adulthood also raised questions regarding the diagnosis of childhood asthma. Laryngomalacia should be distinguished from severe asthma.