ABSTRACT
INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.
Subject(s)
Dexamethasone , Histiocytosis, Langerhans-Cell , Zoledronic Acid , Humans , Histiocytosis, Langerhans-Cell/drug therapy , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/mortality , Child , Adolescent , Japan , Adult , Dexamethasone/therapeutic use , Dexamethasone/administration & dosage , Young Adult , Zoledronic Acid/therapeutic use , Male , Female , Clinical Trials, Phase II as Topic , Child, Preschool , Bone Density Conservation Agents/therapeutic useSubject(s)
Hematopoietic Stem Cell Transplantation , Lymphohistiocytosis, Hemophagocytic , Humans , Child , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Etoposide/therapeutic use , Palmitates , Hematopoietic Stem Cell Transplantation/adverse effects , DexamethasoneABSTRACT
PURPOSE: Heterozygous dominant-negative (DN) STAT1 variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan. METHODS: An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells. RESULTS: Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by Mycobacterium bovis bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in STAT1, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT STAT1. CONCLUSION: Four kindred MSMD subjects with 3 novel variants and 1 known variant in STAT1 were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.
Subject(s)
Mycobacterium Infections , Mycobacterium bovis , Male , Female , Humans , Adult , Infant , Child , Abscess , BCG Vaccine , East Asian People , Mutation , Mycobacterium Infections/diagnosis , Mycobacterium Infections/genetics , Anti-Bacterial Agents , Genetic Predisposition to Disease , STAT1 Transcription Factor/geneticsABSTRACT
Previous research indicates that human genetic diversity in Wallacea-islands in present-day Eastern Indonesia and Timor-Leste that were never part of the Sunda or Sahul continental shelves-has been shaped by complex interactions between migrating Austronesian farmers and indigenous hunter-gatherer communities. Yet, inferences based on present-day groups proved insufficient to disentangle this region's demographic movements and admixture timings. Here, we investigate the spatio-temporal patterns of variation in Wallacea based on genome-wide data from 16 ancient individuals (2600-250 years BP) from the North Moluccas, Sulawesi and East Nusa Tenggara. While ancestry in the northern islands primarily reflects contact between Austronesian- and Papuan-related groups, ancestry in the southern islands reveals additional contributions from Mainland Southeast Asia that seem to predate the arrival of Austronesians. Admixture time estimates further support multiple and/or continuous admixture involving Papuan- and Asian-related groups throughout Wallacea. Our results clarify previously debated times of admixture and suggest that the Neolithic dispersals into Island Southeast Asia are associated with the spread of multiple genetic ancestries.
Subject(s)
Asian People , Asia, Southeastern , Humans , IndonesiaABSTRACT
Although clinical trials have reported an improvement in the prognosis of hemophagocytic lymphohistiocytosis (HLH), current treatment outcomes are unsatisfactory, especially in severe cases. Most clinical trial patients with severe disease discontinue participation due to complications associated with HLH or treatment-related toxicity. A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial was conducted to review the detailed course of these cases to optimize HLH treatment and supportive care. Findings in these patients were compared with those of 45 patients who completed the protocol treatment. The 3 year overall survival rate of patients who completed treatment was 86.7%, versus 50.7% for those who did not complete treatment. Incidence of serious adverse events, such as infections, coagulopathy, and posterior reversible encephalopathy syndrome, during the initial 8 weeks of treatment was much higher in patients who did not complete treatment than in patients who completed treatment. To improve overall outcomes of patients with HLH, it is important to not only optimize HLH-directed therapy but also provide appropriate supportive care.
Subject(s)
Clinical Trials as Topic , Lymphohistiocytosis, Hemophagocytic , Patient Dropouts , Humans , Lymphohistiocytosis, Hemophagocytic/therapy , Posterior Leukoencephalopathy Syndrome , Retrospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: Primary myelofibrosis (PMF) is a clonal stem cell disorder characterized by myeloid dominant hematopoiesis and dysregulated proliferation of fibroblasts in the bone marrow. However, how these aberrant myeloid cells and fibroblasts are produced remains unclear. AIM AND METHODS: In this study, we examined in vivo engraftment kinetics of PMF patient-derived CD34+ cells in immunecompromised NOD/SCID/IL2rgKO (NSG) mice. Engrafted human cells were analyzed with flow cytometry, and proliferation of fibroblastic cells and bone marrow fibrosis were assessed with the histo-pathological examination. RESULTS: Transplantation of PMF patient-derived circulating CD34+ fractions into NSG newborns recapitulates clinical features of human PMF. Engraftment of human CD45+ leukocytes resulted in anemia and myeloid hyperplasia accompanied by bone marrow fibrosis by six months post-transplantation. Fibrotic bone marrow contained CD45-vimentin+ cells of both human and mouse origin, suggesting that circulating malignant CD34+ subsets contribute to myelofibrotic changes in PMF through direct and indirect mechanisms. CONCLUSION: A patient-derived xenotransplantation (PDX) model of PMF allows in vivo examination of disease onset and propagation originating from immature CD34+ cells and will support the investigation of pathogenesis and development of therapeutic modalities for the disorder.
Subject(s)
Antigens, CD34/analysis , Bone Marrow/pathology , Hematopoiesis , Myeloid Cells/pathology , Primary Myelofibrosis/pathology , Animals , Antigens, CD34/blood , Cells, Cultured , Fibrosis , Humans , Mice, Inbred NOD , Mice, SCID , Primary Myelofibrosis/bloodABSTRACT
RATIONALE: Paraganglioma (PGL), an extra-adrenal pheochromocytoma, is a rare tumor, especially in children. While hypersecretion of catecholamines causes the classic triad of headaches, palpitations, and profuse sweating, prompt diagnosis is still challenging. PATIENT CONCERNS: For 7 months, an 8-year-old boy complained of polyuria and weight loss, followed by proteinuria and headache for 1 month prior to admission. He was admitted to our hospital due to an afebrile seizure. DIAGNOSIS: His blood pressure remained markedly elevated even after cessation of the convulsion. Magnetic resonance imaging of the brain revealed posterior reversible encephalopathy syndrome. Abdominal computed tomography showed a mass lesion encasing the left renal artery, measuring 41âmm in length along its major axis. The plasma and urine levels of normetanephrine were elevated. Additionally, iodine-123-metaiodobenzylguanidine scintigraphy showed an abnormal uptake in the abdominal mass with no evidence of metastasis. Based on these findings, we tentatively diagnosed him with PGL. INTERVENTION: Substantial alpha- and beta-blocking procedures were performed, followed by a tumor resection and an extended left nephrectomy on day 31 of hospitalization. Pathological findings confirmed the diagnosis of PGL. OUTCOME: The postoperative course was uneventful, and his blood pressure normalized without the use of antihypertensive agents. Genetic testing revealed a known SDHB germline mutation. The same mutation was also detected on his father and paternal grandfather without any history of hypertension or malignant tumor. LESSON: It remains challenging to diagnose pheochromocytoma/paraganglioma (PPGL) promptly because PPGL can present with a variety of symptoms. Preceding symptoms of the presented case might be caused by PGL. Although PPGL is a rare disease, especially in children, it should be considered in differential diagnosis when various unexplained symptoms persist.
Subject(s)
Adrenal Gland Neoplasms , Catecholamines/blood , Paraganglioma/genetics , Pheochromocytoma , Posterior Leukoencephalopathy Syndrome , 3-Iodobenzylguanidine , Child , Headache/etiology , Humans , Male , Paraganglioma/diagnosis , Paraganglioma/surgery , Pheochromocytoma/diagnosis , Pheochromocytoma/genetics , Pheochromocytoma/surgery , Polyuria/etiology , Proteinuria/etiology , Radionuclide Imaging , Weight LossABSTRACT
Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
Subject(s)
Germ-Line Mutation , Loss of Heterozygosity , Neoplasms, Multiple Primary/genetics , Neuroblastoma/genetics , Ovarian Neoplasms/genetics , Teratoma/genetics , Adolescent , F-Box Proteins/genetics , Female , Homozygote , Humans , Neoplasms, Multiple Primary/drug therapy , Neoplasms, Multiple Primary/pathology , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Retinoblastoma-Like Protein p130/genetics , Teratoma/drug therapy , Teratoma/pathology , Exome SequencingABSTRACT
BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
Subject(s)
Apoptosis/drug effects , Apoptosis/genetics , Drug Resistance, Neoplasm/genetics , Gene Rearrangement , Histone-Lysine N-Methyltransferase/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , Gene Expression Profiling , Gene Expression Regulation, Leukemic , Humans , Immunohistochemistry , Mice , Mice, Knockout , Pyrimidines/pharmacology , Pyrroles/pharmacology , Steroids/pharmacology , Steroids/therapeutic use , Xenograft Model Antitumor AssaysSubject(s)
COVID-19/epidemiology , Mucocutaneous Lymph Node Syndrome/epidemiology , COVID-19/diagnosis , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infection Control/methods , Japan/epidemiology , Male , Mucocutaneous Lymph Node Syndrome/diagnosis , Pandemics , Prevalence , Retrospective Studies , SARS-CoV-2ABSTRACT
There has been little study on the effect of Asian dust exposure on respiratory symptoms among children who are vulnerable to environmental factors. In this panel study, we investigated the effect of Asian dust on respiratory symptoms among children with and without asthma, and their sensitivity. Children attending two elementary schools (137 total), and 23 children with asthma from cooperating medical institutions in Fukuoka prefecture were recruited. Subjects measured peak expiratory flow rate (PEF), and recorded asthma-like symptoms, cough, nasal symptoms and use of medication in a diary from April 1, 2013 to June 30, 2013. To assess exposure to Asian dust, we used Light Detection and Ranging (LIDAR) data. For the analysis of the association between Asian dust and respiratory symptoms, the case-crossover design and generalized estimating equation (GEE) models were used. Taking individual sensitivity to respiratory aggravation into consideration, the subjects were classified into three groups: children without asthma, children with asthma who do not use long-term preventive medication (CA) and children with asthma who use long-term preventive medication (CA-LTM). For CA, Asian dust exposure was significantly associated with asthma-like symptoms, with a hazard ratio of 5.17 (95%CI: 1.02=26.12) at Lag0, and the change in %maxPEF, -1.65% (95%CI:-2.82, -0.48) at Lag0. For children without asthma, a statistically significant association was found between Asian dust exposure and the change in %maxPEF, -0.56% (95%CI: -1.31, -0.08) at Lag1. However, no adverse effects were observed in CA-LTM. Temperature had significant effects on %maxPEF for three groups. Asian dust, photochemical oxidant and pollen caused simultaneously additive adverse effects on nasal symptoms for children without asthma. This study suggests the possibility that long-term preventive medication to manage asthma may suppress aggravation of respiratory symptoms due to Asian dust and may be an effective prevention.
Subject(s)
Asthma , Dust , Asthma/epidemiology , Child , Cross-Over Studies , Humans , Peak Expiratory Flow Rate , PollenABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia. In another patient, although severe hepatic failure, which developed and worsened before the administration of ruxolitinib, was irreversible, rapid improvement in fever, leukopenia and hyperferritinemia was observed. Of note, multiplex cytokine profiling showed amelioration of cytokine storm in both patients. Ruxolitinib may be an encouraging option for HCT-associated HLH.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Pyrazoles/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child, Preschool , Disease Management , Disease Susceptibility , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Nitriles , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines , Transplantation, Homologous , Treatment OutcomeABSTRACT
The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.
Subject(s)
Cell Differentiation , Gene Knock-In Techniques , Interleukin-15/blood , Interleukin-15/genetics , Interleukin-7/blood , Interleukin-7/genetics , Killer Cells, Natural/physiology , Animals , CD56 Antigen/metabolism , Female , Fetal Blood/cytology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Models, Animal , Thymus Gland/cytology , Transcriptome , Transplantation, HeterologousABSTRACT
BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34+CD38-CD45RA- haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34- cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.
Subject(s)
Graft vs Host Disease/immunology , Interleukin-6/genetics , Macrophages/immunology , T-Lymphocytes/immunology , Acute Disease , Animals , Animals, Newborn , Chronic Disease , Disease Models, Animal , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Keratinocytes/cytology , Keratinocytes/metabolism , Macrophages/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Survival Rate , T-Lymphocytes/metabolism , TranscriptomeABSTRACT
Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8+ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3+ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.
Subject(s)
Adenocarcinoma/immunology , CD8-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Tumor Escape/immunology , Aged , Female , Humans , Immunity, Mucosal/immunology , Immunologic Surveillance/immunology , Intestinal Mucosa/immunology , Male , Middle Aged , Programmed Cell Death 1 ReceptorABSTRACT
OBJECTIVE: In recent years, air pollutant concentrations in Japan have decreased slightly; however, there are growing concerns about the influences of transnational air pollution on respiratory illness. We aimed to clarify the short-term association between the ambient air pollution and respiratory symptoms among children without asthma, children with asthma not using long-term medications (CA-nonLTM), and those using them (CA-LTM). METHODS: A total of 138 children attending 2 primary schools and 71 children with asthma regularly visiting cooperating medical institutions were recruited. Study participants measured peak expiratory flow (PEF) twice a day and recorded coughing, nasal symptoms, and medication use in a diary. Predicted associations between daily air pollutant concentrations and respiratory symptoms, and PEF were evaluated using case-crossover and generalized estimate equation models. RESULTS: Changes in %maxPEF per 10 ppb oxidant (Ox) increase in children without asthma, CA-nonLTM, and CA-LTM were -0.26% (95% CI: -0.49, -0.03), -0.51% (95% CI: -0.89, -0.12), and -0.20% (95% CI: -0.42, 0.01), respectively. The odds ratios for coughing per 10 ppb Ox increase in the Lag0 model were 1.34 (95% CI: 1.11, 1.60), 1.52 (95% CI: 1.12, 2.07), and 1.06 (95% CI: 0.93, 1.20), respectively. These suggested that the Ox concentration has graded effects on %maxPEF and coughing, in the following descending order, CA-nonLTM, children without asthma, and CA-LTM. The Ox concentration was also positively associated with nasal symptoms in children without asthma and CA-LTM. CONCLUSION: Our results suggest that using long-term medications to manage asthma may play an important role in preventing exacerbation of respiratory symptoms due to air pollution.