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We present a 19-year-old woman, a case of Lemierre syndrome, who presented with fever, sore throat, and left shoulder pain. Imaging revealed a thrombus in the right internal jugular vein, multiple nodular shadows below both pleura with some cavitations, right lung necrotizing pneumonia, pyothorax, abscess in the infraspinatus muscle, and multiloculated fluid collections in the left hip joint. After inserting a chest tube and administering urokinase for the pyothorax, a bronchopleural fistula was suspected. The fistula was identified based on clinical symptoms and computed tomography scan findings. If a bronchopleural fistula is present, thoracic lavage should not be performed as it may cause complications such as contralateral pneumonia due to reflux. [ABSTRACT FROM AUTHOR]

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Waterproofing spray-associated lung injury (WALI) is an acute respiratory disorder characterized by bilateral diffuse lung injury on chest computed tomography (CT). In most cases, the symptoms and abnormal radiographic findings of WALI patients improve spontaneously over several days; however, some cases have persistent symptoms and abnormal shadows for >1 week. The distinctive features of each WALI are unknown. Herein, we present two new cases of WALI that we encountered in our hospital, and we previously reported two other cases of WALI. We examined the characteristics of WALI in our cases and 39 other cases of WALI definitively diagnosed and reported in PubMed and the Japan medical board with verifiable data during a 15-year period. We compared the clinical characteristics of the 22 cases in which the patients' symptoms were resolved within 1 week (early improvement) to those of the 21 cases in which the symptoms were resolved after >1 week (delayed improvement). The WALI cases with delayed improvement had significantly more shadowing that extended over the entire lung field and was not biased in intensity toward the upper or lower lung field. In addition, the serum white blood cell (WBC) counts and serum Krebs von den Lungen-6 (KL-6) levels differed significantly between the cases of early and delayed improvement of WALI.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., (© 2022. The Author(s).)

Objectives: Mycobacterium avium complex pulmonary disease (MAC-PD) can be serologically diagnosed according to the presence of anti-glycopeptidolipid (GPL)-core IgA antibodies. However, few studies have examined the association between serum anti-GPL-core IgA antibody titers and the clinical characteristics of patients with MAC-PD., Methods: From April 2014 to June 2019, the levels of anti-GPL-core IgA antibodies in 489 MAC-PD patients were determined at the current institute. Of them, 89 patients fulfilled the criteria of the American Thoracic Society and the Infectious Diseases Society of America statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Patients were categorized into the antibody strong-positive (n = 27), weak-positive (n = 32), and negative (n = 30) groups according to their serum anti-GPL-core IgA antibody results. Their clinical characteristics were retrospectively compared., Results: Disease progression requiring treatment and extensive radiological findings were significantly abundant in the strong-positive group compared with the weak-positive group. Clinical characteristics of the antibody weak-positive and negative groups did not significantly differ., Conclusions: The findings revealed that serum anti-GPL-core IgA antibody titers are useful for diagnosing MAC-PD and also for predicting the risk of exacerbation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

No previous studies have examined Mycobacterium avium complex pulmonary disease (MAC-PD) in only elderly patients ⩾75 years old. Here, we investigated the exacerbating factors of MAC-PD in elderly patients and clarified cases that can be followed up without MAC medication. From April 2011 to March 2019, 126 advanced aged patients at our institute were newly diagnosed with MAC-PD, and could be observed based on radiological findings for over a year. Their medical records were retrospectively examined for clinical and radiological findings at the time of diagnosis and 1 year later. To identify the predictors of exacerbation, clinical characteristics of 109 treatment-naïve patients were compared between exacerbated and unchanged groups. Additionally, the unchanged group was followed for one more year. In the current study, positive acid-fast bacilli smears from the sputum test, the presence of cavitary lesions and extensive radiological findings, particularly abnormal shadows in ⩾3 lobes, were predictive of exacerbation among treatment-naïve elderly MAC-PD patients. In the unchanged group, <10% showed exacerbation of radiological findings within the subsequent year. In conclusion, if the sputum smear is negative, no cavitary lesions are present, and abnormal shadows are restricted to ⩽2 lobes, elderly patients with MAC-PD may remain untreated for a few years.

Background and Objectives: The number of patients with pulmonary Mycobacterium avium complex (MAC) disease is increasing worldwide, especially among middle-aged women and never-smokers. However, little is known about the factors causing exacerbations of pulmonary MAC disease in untreated patients. The aim of the present study was to identify the predictors of radiological aggravations of pulmonary MAC disease., Methods: From April 2011 to December 2018, 238 MAC patients at our institute were newly diagnosed with pulmonary MAC disease according to the 2007 American Thoracic Society/Infectious Disease Society guideline. Their medical records were examined retrospectively for their clinical findings. The radiological findings at the time of the diagnosis and 1 year later were evaluated. To identify the predictors of radiological aggravation, multivariable analysis was performed with the data of 167 treatment-naïve patients., Results: Female, never-smoker, and nodular/bronchiectatic (NB) type were predominant in patients with pulmonary MAC disease. Univariate analysis of data from treatment-naïve subjects showed that no lung diseases other than MAC, extensive radiological findings, and a positive acid-fast bacilli (AFB) smear were significantly associated with radiological aggravations. On multivariate analysis, the radiological factor (larger affected area) and absence of other lung disease were significantly associated with radiological aggravations. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations., Conclusions: In this study, the presence of extensive radiological findings and the absence of lung diseases other than MAC were predictors of radiological aggravations of treatment-naïve pulmonary MAC disease. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations., Competing Interests: The authors have declared that no competing interests exist.

Background: Organizing pneumonia (OP) usually responds spectacularly well to initial treatment, but relapses can occur and some cases run a fatal course. Still, the issue of relapse has been addressed in relatively few studies, and predictors have not been clarified. The purpose of this study was to examine the pattern of relapses in OP, to determine whether relapse affects morbidity and mortality, and to identify possible predictors of relapse., Methods: Blood sampling, pulmonary function testing, computed tomography (CT) of the chest, and bronchofiberscopy were performed for all patients and were retrospectively reviewed along with clinical information. Periodical chest CT was conducted and additional chest CT was performed when relapse of OP was clinically suspected. All patients were followed regarding treatment response, treatment duration, and presence of relapse. Results were compared between two groups based on serum concentrations of surfactant protein (SP)-D: normal SP-D and high SP-D., Results: Twenty-two patients were analyzed in this study. SP-D showed a negative correlation with percutaneous oxygen saturation and positive correlations with serum lactate dehydrogenase, Krebs von den Lungen (KL)-6, and percentage of lymphocytes in bronchoalveolar lavage (BAL). Prognosis was good for all patients, but relapse was significantly more frequent in the high SP-D group (6 cases) than in the normal SP-D group (0 cases; P = 0.049). Serum KL-6 and percentage of monocytes in BAL were significantly higher, and pulmonary vital capacity and forced expiratory volume in 1 s were significantly lower in the high SP-D group than in the low SP-D group., Conclusions: When treating cases of OP with high serum concentrations of SP-D, attention should be paid to the possibility of relapse., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Annals of Thoracic Medicine.)

Objectives: International guidelines recommend the use of long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease (COPD), but the usefulness of short-acting bronchodilator assist use for stable COPD remains uncertain. The purpose of the present study was to objectively demonstrate the effects of assist use of procaterol, a short-acting β2-agonist, on the respiratory mechanics of stable COPD patients treated with a long-acting bronchodilator using forced oscillation technique (FOT) and conventional spirometry. We also confirmed the length of time for which procaterol assist could significantly improve the pulmonary function., Methods: We enrolled 28 outpatients with mild to severe COPD (Global Initiative for Obstructive Lung Disease stages I-III), who had used the same long-acting bronchodilator for longer than 3 months and who were in stable condition. All measures were performed using both FOT and spirometry sequentially from 15 min to 2 h after inhalation., Results: Compared to baseline, inhaled procaterol assist use modestly but significantly improved spirometric and FOT measurements within 2 h after inhalation. These significant effects continued for at least 2 h. -Significant correlations were found between parameters -measured by spirometry and those measured by FOT., Conclusions: Procaterol assist use modestly but significantly improved pulmonary function determined by spirometry and respiratory mechanics in patients with stable COPD treated with long-acting bronchodilators. Thus, inhaled procaterol has the potential for assist use for COPD., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Prevention and effective treatment of radiation-induced pneumonitis (RP) could facilitate greater use of radiation therapy (RT) for lung cancer. The purpose of this study was to determine clinical parameters useful for early prediction of RP., Methods: Blood sampling, pulmonary function testing, chest computed tomography, and bronchoalveolar lavage (BAL) were performed in patients with pathologically confirmed lung cancer who had completed ≥60 Gy of RT, at baseline, shortly after RT, and at 1 month posttreatment., Results: By 3 months post-RT, 11 patients developed RP (RP group) and the remaining 11 patients did not (NRP group). RT significantly increased total cell counts and alveolar macrophages in BAL of the NRP group, whereas lymphocyte count was increased in both groups. Matrix metallopeptidase-9 (MMP-9) increased and vascular endothelial growth factor decreased significantly in the BAL fluid (BALF) of the RP group following RT. Serum surfactant protein D (SP-D) increased significantly in the NRP group. SP-D in BALF from the RP group increased significantly with a subsequent increase in serum SP-D. Pulmonary dilution decreased similarly in both groups of patients., Conclusions: Increased SP-D in BALF, rather than that in serum, could be useful biomarkers in predicting RP. The MMP-9 in BALF might play a role in the pathogenesis of RP. Pulmonary dilution test may not be predictive of the development of RP., Competing Interests: There are no conflicts of interest.

Introduction: Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting β2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti-inflammatory and anti-remodeling effects., Areas Covered: Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy., Expert Opinion: Whether or not tiotropium has anti-inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma.

A 70-year-old female presented with yellow discoloration of the nail beds of all fingers and toes, as well as bilateral pleural effusions. The patient was diagnosed as having the yellow nail syndrome based on the triad of yellow nails, lymphedema, and pleural effusions. The patient's intractable bilateral pleural effusion was treated with pleurodesis using OK-432. The treatment prevented the accumulation of pleural fluid for a long period of time. Pleural effusion associated with yellow nail syndrome is thought to be difficult to treat; however, this patient's excellent clinical course suggests that pleurodesis with OK-432 could be used to treat the disease in the future.

A 76-year-old man, who was in the hospital for the treatment of type 2 diabetes mellitus and was receiving gonadotropin-releasing hormone (GnRH) agonist treatment for prostate cancer, developed fever and hypoxemia. Imaging revealed diffuse interstitial shadows, and PCR of the bronchoalveolar lavage fluid was positive for Pneumocystis jirovecii. The patient's absolute CD4-positive lymphocyte count dropped to 145/microl, but the HIV antibody was negative. After trimethoprim-sulfamethoxazole (TMP/SXT) treatment, the absolute CD4 positive lymphocyte count returned to normal. This patient with type 2 diabetes mellitus developed Pneumocystis pneumonia and developed a transient decrease in CD4-positive lymphocytes.

In a human immunodeficiency virus type 1 (HIV-1)-infected individual, immune-pressure-mediated positive selection operates to maintain the antigenic polymorphism on the gp120 third variable (V3) loop. Recently, we suggested on the basis of sequencing C2/V3 segments from an HIV-1 subtype E-infected family that a V3 sequence lineage group of the non-syncytium-inducing (NSI) variants (group 1) was relatively resistant to positive selection pressure (35). To better understand the relationship between the intensity of positive selection pressure and cell tropism of the virus, we determined the linkage between each V3 genotype and its function of directing coreceptor preference and MT2 cell tropism. The biological characterization of a panel of V3 recombinant viruses showed that all of the group 1 V3 sequences could confer an NSI/CCR5-using (NSI/R5) phenotype on HIV-1(LAI), whereas the group 2 V3 sequence, which was more positively charged than the group 1 sequence, dictated mainly a syncytium-inducing, CXCR4-using (SI/X4) phenotype. Phylogenetic analysis of C2/V3 sequences encoding group 1 or 2 V3 suggested that the variants carrying group 1 V3 are the ancestors of the intrafamilial infection and persisted in the family, while the variants carrying group 2 V3 evolved convergently from the group 1 V3 variants during disease progression in the individuals. Finally, a statistical test showed that the V3 sequence that could dictate an NSI/R5 phenotype had a synonymous substitution rate significantly higher than the nonsynonymous substitution rate. These data suggest that V3 sequences of the subtype E NSI/R5 variants are more resistant to positive selection pressure than those of the SI/X4 variants.

It has been suggested that immune-pressure-mediated positive selection operates to maintain the antigenic polymorphism on the third variable (V3) loop of the gp120 of human immunodeficiency virus type 1 (HIV-1). Here we present evidence, on the basis of sequencing 147 independently cloned env C2/V3 segments from a single family (father, mother, and their child), that the intensity of positive selection is related to the V3 lineage. Phylogenetic analysis and amino acid comparison of env C2/V3 and gag p17/24 regions indicated that a single HIV-1 subtype E source had infected the family. The analyses of unique env C2/V3 clones revealed that two V3 lineage groups had evolved in the parents. Group 1 was maintained with low variation in all three family members regardless of the clinical state or the length of infection, whereas group 2 was only present in symptomatic individuals and was more positively charged and diverse than group 1. Only virus isolates carrying the group 2 V3 sequences infected and induced syncytia in MT2 cells, a transformed CD4(+)-T-cell line. A statistically significant excess of nonsynonymous substitutions versus synonymous substitutions was demonstrated only for the group 2 V3 region. The data suggest that HIV-1 variants, possessing the more homogeneous group 1 V3 element and exhibiting the non-syncytium-inducing phenotype, persist in infected individuals independent of clinical status and appear to be more resistant to positive selection pressure.