A Cluster of Paragonimiasis with Delayed Diagnosis Due to Difficulty Distinguishing Symptoms from Post-COVID-19 Respiratory Symptoms: A Report of Five Cases.

Paragonimiasis caused by trematodes belonging to the genus Paragonimus is often accompanied by chronic respiratory symptoms such as cough, the accumulation of sputum, hemoptysis, and chest pain. Prolonged symptoms, including respiratory symptoms, after coronavirus disease 2019 infection (COVID-19) are collectively called post-COVID-19 conditions. Paragonimiasis and COVID-19 may cause similar respiratory symptoms. We encountered five cases of paragonimiasis in patients in Japan for whom diagnoses were delayed due to the initial characterization of the respiratory symptoms as a post-COVID-19 condition. The patients had consumed homemade drunken freshwater crabs together. One to three weeks after consuming the crabs, four of the five patients were diagnosed with probable COVID-19. The major symptoms reported included cough, dyspnea, and chest pain. The major imaging findings were pleural effusion, pneumothorax, and nodular lesions of the lung. All the patients were diagnosed with paragonimiasis based on a serum antibody test and peripheral blood eosinophilia (560-15,610 cells/µL) and were treated successfully with 75 mg/kg/day praziquantel for 3 days. Before diagnosing a post-COVID-19 condition, it is necessary to consider whether other diseases, including paragonimiasis, may explain the symptoms. Further, chest radiographic or blood tests should be performed in patients with persistent respiratory symptoms after being infected with COVID-19 to avoid overlooking the possibility of infection.

Overweight improves long-term survival in Japanese patients with asthma.

BACKGROUND: Obesity is a risk factor for severe and difficult-to-treat asthma. However, the impact of different physiques on long-term outcomes is poorly understood. We aimed to investigate the correlation between obesity and asthma-associated long-term mortality in Japanese adults. METHODS: From the data on 3146 individuals with air pollution-related respiratory diseases in the Omuta City Air Pollution-Related Health Damage Cohort Program, 697 adult patients with asthma were analyzed. Hazard ratios for long-term all-cause and respiratory disease -related mortality were compared in patients with different physiques using the Cox proportional hazard models. The classification of physiques was based on the WHO obesity criteria. RESULTS: Of the 697 patients, 439 died during the median observation period of 26.3 years. The number (% of total) of underweight, normal-weight, pre-obese, and obese class I-III individuals were 75 (10.8%), 459 (65.9%), 140 (20.1%), and 23 (3.3%), respectively. The Cox proportional hazard model (adjusted hazard ratio [95% confidence interval], P value) showed that pre-obese group had a significantly reduced risk for all-cause (0.65 [0.51 to 0.83], P < 0.05) and respiratory disease (0.55 [0.37 to 0.81], P < 0.05)-related mortality related to normal-weight group. CONCLUSIONS: Our cohort program demonstrated that being slightly overweight may reduce the risk of long-term mortality in patients with asthma. However, the influence of obesity on long-term outcomes remains unclear in asthma, because of the small number of obese patients included in our study. Our findings suggest that interventions, including nutrition and exercises, should be provided to Japanese patients with asthma.

The progression of comorbidity in IL-18 transgenic chronic obstructive pulmonary disease mice model.

Patients with severe COPD are known to have comorbidities such as emaciation, cor pulmonale and right heart failure, muscle weakness, hyperlipemia, diabetes mellitus, osteoporosis, muscle atrophy, arterial sclerosis, hypertension, and depression. Therefore, treatment for COPD needs to focus on these comorbidities as well as the lungs. We previously reported a new mouse model of COPD utilizing the human surfactant protein C promoter SP-C to drive the expression of mature mouse IL-18 cDNA; constitutive IL-18 overproduction in the lungs of transgenic (Tg) mice induces severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension with aging. In the present study, we evaluated the progression of comorbidity in our COPD model. In female Tg mice, significant weight loss was observed at 16 weeks and beyond, when compared with control wild-type (WT) mice. This weight loss was suppressed in IL-13-deficient (knockout; KO) Tg mice. Muscle weight and bone mineral density were significantly decreased in aged Tg mice relative to control WT and IL-13 KO Tg mice. The aged Tg mice also showed impaired glucose tolerance. IL-18 and IL-13 may play important roles in the pathogenesis of comorbidity in COPD patients.

A Case of STAT1 Mutations in Chronic Mucocutaneous Candidiasis Diagnosed in an Adult.

A 30-year-old man presented with oral candidiasis and a history of lung abscess. He experienced recurring oral and skin candidiasis in childhood but spent long periods without any infections. Therefore, immunodeficiency was suspected. T and B lymphocyte and natural killer cell counts as well as immunoglobulin levels were normal. Human immunodeficiency virus test results were negative. Therefore, we suspected chronic mucocutaneous candidiasis (CMC). The signal transducer and activator of transcription (STAT) mutation, the leading cause of CMC, was detected by exome sequencing. Most cases of STAT-1 mutations are diagnosed in childhood, but a few are diagnosed in adulthood because Candida infections may not be severe.

Poor Asthma Control in Schoolchildren May Lead to Lower Lung Function Trajectory from Childhood to Early Adulthood: A Japanese Cohort Study.

Purpose: Although childhood asthma is a risk factor for adult lung function disorders, the correlation between childhood asthma control level and lung function growth remains unclear in Japan. The correlation between childhood asthma control and early adulthood lung function growth was investigated in this study. Patients and Methods: We included 505 children with asthma from the Omuta City Air Pollution-Related Health Damage Cohort Program. The characteristics and lung function of girls and boys aged 6-11 years and 12-17 years were compared between poor and good asthma control groups. Results: Among the 505 children, 214 (42.4%) showed poor asthma control. The mean percentage forced expiratory volume in 1 second predicted for girls and boys aged 6-11 years (80.2% and 79.2%, respectively) and 12-17 years (80.0% and 81.1%, respectively) in the poor control group was significantly lower than those of girls and boys aged 6-11 years (87.9% and 87.3%, respectively) and 12-17 years (88.1% and 87.8%, respectively) in the good control group. However, a linear regression model did not reveal between-group differences in the slopes of lung function growth for both sexes. Girls (24.6%, P < 0.0001) and boys (24.4%, P = 0.0026) in the poor control group had a significantly higher proportion of young adults with obstructive ventilatory patterns than girls (1.4%) and boys (8.1%) in the good control group. Conclusion: Our findings revealed that poor childhood asthma control leaded to lung function disorders, which suggest the importance of early asthma control in school children.

The contribution of FEV1 and airflow limitation on the intensity of dyspnea and leg effort during exercise. Insights from a real-world cohort.

RATIONALE: The effort required to cycle and breathe intensify as power increases during incremental exercise. It is currently unclear how changes in FEV1 in the presence or absence of airflow limitation) impacts the intensity of dyspnea and leg effort. This is clinically important as the improvement in FEV1 is often the target for improving dyspnea. OBJECTIVES: To investigate the relationship between dyspnea (D), leg effort, power (P), and FEV1 with and without airflow limitation using direct psychophysical scaling performed during incremental exercise testing to symptom limited capacity. METHODS: Retrospective analysis of consecutive patients over the age of 35 referred for cardio-pulmonary exercise testing at McMaster University Medical Centre from 1988-2012.The modified Borg scale was used to measure dyspnea throughout incremental exercise testing. MEASUREMENTS AND RESULTS: 38,788 patients were included in the analysis [Mean Age 58.6 years (SD ±11.8), Males 61%, BMI 28.1 kg/m2 (SD ±5.1), FEV1 was 2.7 L (SD ±0.85), 95% predicted (SD ±20.4), FVC 3.4 L (SD ± 1.0), 94% predicted (SD ±17.0)], and 10.9% had airflow limitation (AL, FEV1 /FVC < 70%). In a nonlinear regression analysis, the intensity of dyspnea increased in a positively accelerating manner with power and as the FEV1 % predicted decreased: Dyspnea = 0.06 * Power1.03  * FEV1 %Pred-0.66 (r = .63). The intensity of leg effort increased with power and declining quadricep strength and FEV1% predicted: Leg Effort = 0.06 * Power1.22  * Quad-0.56 *FEV1 %Pred-0.39 (r = .73). There was no independent effect of AL on dyspnea of leg effort. CONCLUSION: Power, quadriceps strength and FEV1 are the dominant factors contributing to dyspnea and leg effort, irrespective of the degree of airflow limitation.

Attenuated Airway Eosinophilic Inflammations in IL-38 Knockout Mouse Model.

BACKGROUND: The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed. METHODS: The numbers of eosinophils and neutrophils, and levels of IL-5, IL-13 and IL-17A protein and mRNA in bronchoalveolar lavage fluid (BALF) and lung tissue were compared between wild-type (WT) and IL-38-KO mice after OVA sensitization and challenge. The effects of additional purified recombinant mouse (rm) IL-38 protein were investigated in the IL-38-KO murine asthma model. RESULTS: The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p<0.05). The number of airway eosinophils in IL-38-KO mice was significantly lower than in WT mice after OVA challenge (p<0.01). BALF analysis confirmed the lower number of airway eosinophils in IL-38-KO mice and showed that this was significantly associated with lower IL-5 protein levels (r=0.92, p<0.0001). However, the additional rm IL-38 protein did not neutralize airway eosinophilia in IL-38-KO mice. CONCLUSION: IL-38 may enhance airway eosinophilic inflammation in asthma through IL-5 induction.

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. METHODS: To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. RESULTS: IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. CONCLUSIONS: IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF.

Evaluation of the Modified Medical Research Council Dyspnea Scale for Predicting Hospitalization and Exacerbation in Japanese Patients with Chronic Obstructive Pulmonary Disease.

OBJECTIVE: The modified Medical Research Council (mMRC) scale is recommended for conducting assessments of dyspnea and disability and functions as an indicator of exacerbation. The aim of this study was to investigate whether the mMRC scale can be used to predict hospitalization and exacerbation in Japanese patients with chronic obstructive pulmonary disease (COPD). METHODS: In a previous 52-week prospective study, 123 patients with COPD were classified into five groups (grades 0 to 4) according to the mMRC scale and four groups (stages I to IV) according to the spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. The frequency and period until the first event of hospitalization and exacerbation were compared among the groups. RESULTS: The population of patients who experienced hospitalization and exacerbation during the 52-week study period, with an mMRC scale grade of 4, 3, 2, 1 and 0 was 50.0 and 100, 55.6 and 88.9, 21.1 and 73.7, 2.6 and 48.7, and 4.0 and 22.0%, respectively. A multivariate analysis adjusted for the GOLD stage and age showed that the patients with an mMRC scale grade of ≥3 had higher frequencies of hospitalization and exacerbation than those with lower grades. Meanwhile, the patients with an mMRC scale grade of ≥2 showed a significantly earlier time until the first exacerbation, but not hospitalization, in comparison with those with grade 0. CONCLUSION: The present results indicate that, among Japanese patients with COPD, those with an mMRC scale grade of ≥3 have a significantly poorer prognosis and that the mMRC scale can be used to predict hospitalization and exacerbation.

IL-38: A new factor in rheumatoid arthritis.

The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans-induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (-/-) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (-/-) mice showed greater disease severity, accompanied by higher IL-1ß and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans.

COPD assessment tests scores are associated with exacerbated chronic obstructive pulmonary disease in Japanese patients.

BACKGROUND: Guidelines recommend chronic obstructive pulmonary disease (COPD) assessment tests (CATs) for evaluation of symptoms and management risks. To investigate whether CAT can predict moderate or severe exacerbations in Japanese COPD patients, a single-blinded prospective study was performed. METHODS: A 123 Japanese COPD patients were classified into high-CAT (n=64) and low-CAT (n=59) groups. The frequencies and periods of moderate or severe exacerbation and hospitalization were compared between the two groups. Multivariate logistic regression analysis was performed to investigate whether CAT could predict exacerbations. A receiver operating characteristic (ROC) curve analysis was employed to find an appropriate CAT score for exacerbation. RESULTS: The high-CAT group was significantly older, had a lower body mass index, and had a lower airflow obstruction as compared to the low CAT group. The frequency of moderate or severe exacerbation (1.3±1.3 events per patient per year, p<0.0001) and hospitalizations (0.2±0.4, p=0.0202) in the high-CAT group was significantly higher than in the low-CAT group (0.4±0.7 and 0.0±0.1, respectively). Multivariate logistic regression analysis showed that both high CAT score and low airflow obstruction were independently predictive of frequent moderate or severe COPD exacerbation. ROC analysis showed that the best cut-off CAT score for moderate or severe COPD exacerbation was 8 points. CONCLUSION: Our present results indicate that COPD Japanese patients showing high CAT scores have a poor prognosis, and that the CAT score is able to predict exacerbation in Japanese COPD.

Overexpression of CD163, CD204 and CD206 on alveolar macrophages in the lungs of patients with severe chronic obstructive pulmonary disease.

We have previously reported that the lungs of patients with very severe chronic obstructive pulmonary disease (COPD) contain significantly higher numbers of alveolar macrophages than those of non-smokers or smokers. M1 and M2 macrophages represent pro- and anti-inflammatory populations, respectively. However, the roles of M1 and M2 alveolar macrophages in COPD remain unclear. Immunohistochemical techniques were used to examine CD163, CD204 and CD206, as M2 markers, expressed on alveolar macrophages in the lungs of patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (mild) n = 11, II (moderate) n = 9, III (severe) n = 2, and IV (very severe) n = 16). Fifteen smokers and 10 non-smokers were also examined for comparison. There were significantly higher numbers of alveolar macrophages in COPD patients than in smokers and non-smokers. The numbers and percentages of CD163(+), CD204(+) or CD206(+) alveolar macrophages in patients with COPD at GOLD stages III and IV were significantly higher than in those at GOLD stages I and II, and those in smokers and non-smokers. In patients with COPD, there was a significant negative correlation between the number of CD163(+), CD204(+) or CD206(+) alveolar macrophages and the predicted forced expiratory volume in one second. Overexpression of CD163, CD204 and CD206 on lung alveolar macrophages may be involved in the pathogenesis of COPD.