Suppressed pediatric asthma hospitalizations during the COVID-19 pandemic in Japan, from a national survey.

BACKGROUND: Acute asthma exacerbation in children is often caused by respiratory infections. In this study, a coordinated national surveillance system for acute asthma hospitalizations and causative respiratory infections was established. We herein report recent trends in pediatric acute asthma hospitalizations since the COVID-19 pandemic in Japan. METHODS: Thirty-three sentinel hospitals in Japan registered all of their hospitalized pediatric asthma patients and their causal pathogens. The changes in acute asthma hospitalization in children before and after the onset of the COVID-19 pandemic and whether or not COVID-19 caused acute asthma exacerbation were investigated. RESULTS: From fiscal years 2010-2019, the median number of acute asthma hospitalizations per year was 3524 (2462-4570), but in fiscal years 2020, 2021, and 2022, the numbers were 820, 1,001, and 1,026, respectively (the fiscal year in Japan is April to March). This decrease was observed in all age groups with the exception of the 3- to 6-year group. SARS-CoV-2 was evaluated in 2094 patients from fiscal years 2020-2022, but the first positive case was not detected until February 2022. Since then, only 36 of them have been identified with SARS-CoV-2, none of which required mechanical ventilation. Influenza, RS virus, and human metapneumovirus infections also decreased in FY 2020. In contrast, 24% of patients had not been receiving long-term control medications before admission despite the severity of bronchial asthma. CONCLUSION: SARS-CoV-2 was hardly detected in children with acute asthma hospitalization during the COVID-19 pandemic. This result indicated that SARS-CoV-2 did not induce acute asthma exacerbation in children. Rather, infection control measures implemented against the pandemic may have consequently reduced other respiratory virus infections and thus acute asthma hospitalizations during this period. However, the fact that many hospitalized patients have not been receiving appropriate long-term control medications is a major problem that should be addressed.

CD226 and TIGIT Cooperate in the Differentiation and Maturation of Human Tfh Cells.

Costimulation pathways play an essential role in T cell activation, differentiation, and regulation. CD155 expressed on antigen-presenting cells (APCs) interacts with TIGIT, an inhibitory costimulatory molecule, and CD226, an activating costimulatory molecule, on T cells. TIGIT and CD226 are expressed at varying levels depending on the T cell subset and activation state. T follicular helper cells in germinal centers (GC-Tfh) in human tonsils express high TIGIT and low CD226. However, the biological role of the CD155/TIGIT/CD226 axis in human Tfh cell biology has not been elucidated. To address this, we analyzed tonsillar CD4+ T cell subsets cultured with artificial APCs constitutively expressing CD155. Here we show that CD226 signals promote the early phase of Tfh cell differentiation in humans. CD155 signals promoted the proliferation of naïve CD4+ T cells and Tfh precursors (pre-Tfh) isolated from human tonsils and upregulated multiple Tfh molecules and decreased IL-2, a cytokine detrimental for Tfh cell differentiation. Blocking CD226 potently inhibited their proliferation and expression of Tfh markers. By contrast, while CD155 signals promoted the proliferation of tonsillar GC-Tfh cells, their proliferation required only weak CD226 signals. Furthermore, attenuating CD226 signals rather increased the expression of CXCR5, ICOS, and IL-21 by CD155-stimulated GC-Tfh cells. Thus, the importance of CD226 signals changes according to the differentiation stage of human Tfh cells and wanes in mature GC-Tfh cells. High TIGIT expression on GC-Tfh may play a role in attenuating the detrimental CD226 signals post GC-Tfh cell maturation.

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

PURPOSE: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. METHODS: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. RESULTS: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. CONCLUSION: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.

Successful management of a Bacillus cereus catheter-related bloodstream infection outbreak in the pediatric ward of our facility.

Bacillus cereus can spread easily in various environments and can contaminate medical environments, such as ventilator equipment, intravascular catheters, and linen. B. cereus is known to infect immunocompromised patients. Although nosocomial B. cereus outbreaks are often reported, effective preventive measures are not clarified. We report an outbreak of B. cereus catheter-related bloodstream infection (CRBSI) in the pediatric ward and aim at identifying risk factors and effective infection control measures for the outbreak. The nurse station at the pediatric ward and blood cultures were assessed. Sterilization of devices has been ensured thereafter. We identified common risk factors including catheter placement for liquid nutrition, use of high-caloric amino-acid-containing infusion fluid, immunocompromised patients, and contact of the catheter route with the floor. Intervention by the Infection Control Team and educating the medical staff regarding methods of disinfection, including scrubbing the facility, helped terminate the outbreak. We discuss a pre-emptive intervention to terminate the outbreak of CRBSI.

Cytokine profiles in Mycoplasma pneumoniae infection-associated hemophagocytic lymphohistiocytosis.

A 3-year-old boy with Mycoplasma pneumoniae infection associated with hemophagocytic lymphohistiocytosis (MP-HLH) presented with an elevated level of serum interleukin-12 (IL-12) and lower levels of interferon-γ and IL-10 compared to patients with Epstein-Barr virus infection associated with HLH (EBV-HLH). Unlike the patients with EBV-HLH, CD8+ CD5low HLA-DR++ T cells were not detected in our pediatric patient. Thus, the pathophysiology of MP-HLH may differ from that of EBV-HLH.

ACTN1 rod domain mutation associated with congenital macrothrombocytopenia.

Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.

Alternaria extract activates autophagy that induces IL-18 release from airway epithelial cells.

Alternaria alternata is a major outdoor allergen that causes allergic airway diseases. Alternaria extract (ALT-E) has been shown to induce airway epithelial cells to release IL-18 and thereby initiate Th2-type responses. We investigated the underlying mechanisms involved in IL-18 release from ALT-E-stimulated airway epithelial cells. Normal human bronchial epithelial cells and A549 human lung adenocarcinoma cells were stimulated with ALT-E in the presence of different inhibitors of autophagy or caspases. IL-18 levels in culture supernatants were measured by ELISA. The numbers of autophagosomes, an LC3-I to LC3-II conversion, and p62 degradation were determined by immunofluorescence staining and immunoblotting. 3-methyladenine and bafilomycin, which inhibit the formation of preautophagosomal structures and autolysosomes, respectively, suppressed ALT-E-induced IL-18 release by cells, whereas caspase 1 and 8 inhibitors did not. ALT-E-stimulation increased autophagosome formation, LC-3 conversion, and p62 degradation in airway epithelial cells. LPS-stimulation induced the LC3 conversion in A549 cells, but did not induce IL-18 release or p62 degradation. Unlike LPS, ALT-E induced airway epithelial cells to release IL-18 via an autophagy dependent, caspase 1 and 8 independent pathway. Although autophagy has been shown to negatively regulate canonical inflammasome activity in TLR-stimulated macrophages, our data indicates that this process is an unconventional mechanism of IL-18 secretion by airway epithelial cells.

IL-33 enhanced the proliferation and constitutive production of IL-13 and IL-5 by fibrocytes.

Interleukin-33 appears to play important roles in the induction of allergic airway inflammation. However, whether IL-33 is involved in airway remodeling remains unclear. Because fibrocytes contribute to tissue remodeling in the setting of chronic inflammation, we examined the effects of IL-33 on fibrocyte functions. Fibrocytes were generated in vitro from peripheral blood mononuclear cells by culturing in the presence of platelet derived growth factors and the cells were stimulated with IL-33. IL-33 enhanced cell proliferation, α-SMA expression, and pro-MMP-9 activity by the fibrocytes without increasing endogenous transforming growth factor-ß1 production. Fibrocytes constitutively expressed IL-13 and IL-5, and their production was augmented by stimulation with IL-33. Dexamethasone inhibited the functions of fibrocytes, but IL-33 made fibrocytes slightly refractory to the inhibitory effect of dexamethasone in terms of IL-13 production. Montelukast suppressed IL-13 production by nonstimulated fibrocytes but not those stimulated by IL-33. These findings suggest that IL-33 is involved in the airway remodeling process through its modulation of fibrocyte function independent of antigen stimulation. IL-33 might partially reduce the therapeutic effects of glucocorticoid and cysteinyl leukotriene receptor antagonist on fibrocyte-mediated Th2 responses.

Pneumothorax in patients with severe combined immunodeficiency.

BACKGROUND: Most infants with pneumothorax have underlying conditions. Pneumocystis jirovecii pneumonia (PCP) frequently occurs in patients with severe combined immunodeficiency (SCID). The aim of this study was to determine clinical features of PCP-associated pneumothorax in SCID patients. METHODS: The medical records of four SCID patients with pneumothorax were retrospectively reviewed. RESULTS: All four patients were diagnosed as having SCID at the time of contracting PCP. All patients received mechanical ventilation because of severe respiratory failure. Only one patient was successfully extubated and was alive following hematopoietic stem cell transplantation (HSCT); of the remaining patients, however, two died of respiratory failure, and one patient died of early HSCT-related complications. CONCLUSIONS: Pneumothorax associated with PCP can occur in SCID patients, and they may have a poor prognosis. If pneumothorax occurs in infants, both respiratory management and prompt investigation of the underlying conditions are needed, considering the possibility of PCP associated with SCID.

Rice protein-induced enterocolitis syndrome with transient specific IgE to boiled rice but not to retort-processed rice.

Described herein is the case of an 8-month-old girl with atypical food protein-induced enterocolitis syndrome due to rice. She presented with vomiting and poor general activity 2 h after ingestion of boiled rice. Oral food challenge test using high-pressure retort-processed rice was negative, but re-exposure to boiled rice elicited gastrointestinal symptoms. On western blot analysis the patient's serum was found to contain IgE bound to crude protein extracts from rice seed or boiled rice, but not from retort-processed rice. The major protein bands were not detected in the electrophoresed gel of retort-processed rice extracts, suggesting decomposition by high-temperature and high-pressure processing. Oral food challenge for diagnosing rice allergy should be performed with boiled rice to avoid a false negative. Additionally, some patients with rice allergy might be able to ingest retort-processed rice as a substitute for boiled rice.

Marked elevation of interleukin-6 in mild encephalopathy with a reversible splenial lesion (MERS) associated with acute focal bacterial nephritis caused by Enterococcus faecalis.

This report describes two cases of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) associated with acute focal bacterial nephritis (AFBN). The patients, who presented with fever and delirious behavior, exhibited hyponatremia and markedly elevated interleukin (IL)-6 in cerebrospinal fluid (CSF) and serum. Enterococcus faecalis was detected in the urine culture. After ampicillin treatment, their consciousness improved without neurological sequelae. Moreover, a diffusion-weighted MRI abnormality, i.e., intensified signals in splenium of the corpus callosum, disappeared. MERS is a possible complication of AFBN. Elevated CSF IL-6 levels suggest that remote activation of intracerebral immune response through the immune-neuroendocrine pathway might play an important role in the pathophysiology of MERS.

Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody.

We report on a 4-year-old boy who developed paroxysmal cold hemoglobinuria (PCH) following the first dose of a seven-valent pneumococcal conjugate vaccine. He was admitted because of dark urine after exposure to cold air. Laboratory tests indicated anemia, increased serum indirect bilirubin and lactate dehydrogenase, and decreased serum haptoglobin. Donath-Landsteiner (D-L) test was positive. The D-L antibody belonged to the IgM class and exhibited anti-P specificity. Symptoms and signs subsided after supportive care without any medication. Although PCH is often associated with viral or bacterial infection and is caused by IgG-class D-L antibodies with anti-P specificity, this case was unique because a D-L antibody of the IgM class with anti-P specificity caused PCH after immunization with a pneumococcal vaccine.