Multiomics analysis identified IL-4-induced IL1RL1high eosinophils characterized by prominent cysteinyl leukotriene metabolism.

BACKGROUND: Clinical studies have demonstrated that IL-4, a type 2 cytokine, plays an important role in the pathogenesis of chronic rhinosinusitis and eosinophilic asthma. However, the direct effect of IL-4 on eosinophils remains unclear. OBJECTIVE: We aimed to elucidate the inflammatory effects of IL-4 on the functions of human eosinophils. METHODS: A multiomics analysis comprising transcriptomics, proteomics, lipidomics, quantitative RT-PCR, and flow cytometry was performed by using blood eosinophils from healthy subjects stimulated with IL-4, IL-5, or a combination thereof. RESULTS: Transcriptomic and proteomic analyses revealed that both IL-4 and IL-5 upregulate the expression of γ-gultamyl transferase 5, a fatty acid-metabolizing enzyme that converts leukotriene C4 into leukotriene D4. In addition, IL-4 specifically upregulates the expression of IL-1 receptor-like 1 (IL1RL1), a receptor for IL-33 and transglutaminase-2. Additional transcriptomic analysis of cells stimulated with IL-13 revealed altered gene expression profiles, characterized by the upregulation of γ-gultamyl transferase 5, transglutaminase-2, and IL1RL1. The IL-13-induced changes were not totally different from the IL-4-induced changes. Lipidomic analysis revealed that IL-5 and IL-4 additively increased the extracellular release of leukotriene D4. In vitro experiments revealed that STAT6 and IL-4 receptor-α control the expression of these molecules in the presence of IL-4 and IL-13. Analysis of eosinophils derived from patients with allergic disorders indicated the involvement of IL-4 and IL-13 at the inflamed sites. CONCLUSIONS: IL-4 induces the proallergic phenotype of IL1RL1high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma.

Corrigendum: 1270 nm near-infrared light as a novel vaccine adjuvant acts on mitochondrial photoreception in intradermal vaccines.

[This corrects the article DOI: 10.3389/fimmu.2022.1028733.].

Noninvasive Ambulatory Electrocardiographic Markers from Patients with COVID-19 Pneumonia: A Report of Three Cases.

Coronavirus disease 2019 (COVID-19) has affected medical practice. More than 7,000,000 patients died worldwide after being infected with COVID-19; however, no specific laboratory markers have yet been established to predict death related to this disease. In contrast, electrocardiographic changes due to COVID-19 include QT prolongation and ST-T changes; however, there have not been studies on the ambulatory electrocardiographic markers of COVID-19. We encountered three patients diagnosed as having COVID-19 who did not have a prior history of significant structural heart diseases. All patients had abnormalities in ambulatory echocardiogram parameters detected by high-resolution 24 h electrocardiogram monitoring: positive late potentials (LPs) and T-wave alternans (TWA), abnormal heart rate variability (HRV), and heart rate turbulence (HRT). Case 1 involved a 78-year-old woman with a history of chronic kidney disease, Case 2 involved a 76-year-old man with hypertension and diabetes, and Case 3 involved a 67-year-old man with renal cancer, lung cancer, and diabetes. None of them had a prior history of significant structural heart disease. Although no significant consistent increases in clinical markers were observed, all three patients died, mainly because of respiratory failure with mild heart failure. The LP, TWA, HRV, and HRT were positive in all three cases with no significant structural cardiac disease at the initial phase of admission. The further accumulation of data regarding ambulatory electrocardiographic markers in patients with COVID-19 is needed. Depending on the accumulation of data, the LP, TWA, HRV, and HRT could be identified as potential risk factors for COVID-19 pneumonia in the early phase of admission.

Massive pleural effusion in porous diaphragm syndrome due to lymphatic leakage after pelvic surgery.

We present the case of a patient who developed a massive right pleural effusion after pelvic surgery, not thoracic surgery. Lymphatic leakage into the abdominal cavity after pelvic surgery can cause massive pleural effusion when complicated with porous diaphragm syndrome.

IgG4-related retroperitoneal fibrosis induced by nivolumab and ipilimumab in a patient with non-small cell lung cancer: A case report.

IgG4-related diseases are adverse events that occur after receiving treatment with immune checkpoint inhibitors (ICI). This study reports the first case of IgG4-related retroperitoneal fibrosis after the administration of chemotherapy with nivolumab and ipilimumab (NI therapy). An 80-year-old man developed lower abdominal pain eight months after NI therapy was initiated. Although the primary lesion maintained its reduced size on computed tomography, there was an increase in the soft tissue shadows intensity around the abdominal aorta, bladder, and seminal vesicles, suggesting retroperitoneal fibrosis. Blood tests showed elevated IgG4 levels. Computed tomography-guided biopsy of the retroperitoneum showed B cell-dominant lymphocyte infiltration consistent with IgG4-related retroperitoneal fibrosis and characteristic CD8-positive lymphocyte infiltration, suggestive of the involvement of cytotoxic T cells. Based on the clinical, imaging, and pathological findings, the patient was diagnosed with IgG4-related retroperitoneal fibrosis due to ICI. Immunotherapy discontinuation alone did not result in improvement; therefore, steroid therapy was initiated. In clinical practice, IgG4-related retroperitoneal fibrosis can occur as an immune-related adverse event when administering anti-PD-1 and anti-CTLA-4 antibodies for cancer immunotherapy. Early steroid therapy could be effective in controlling this immune-related adverse event.

Successful Chemotherapy for Diffuse Cystic Lung Metastases during Targeted Therapy with Osimertinib in a Patient with Non-Small-Cell Lung Cancer: A Literature Review and a Rare Case Report.

Introduction: Diffuse lung cysts occur owing to several diseases; however, diffuse cystic lung metastases are very rare in the case of lung cancer. We report a rare case of diffuse cystic lung metastases from lung adenocarcinoma and reviewed previously reported cases of cystic lung metastases for lung cancer and determined their characteristics. Case Presentation: A 78-year-old Japanese woman with advanced lung adenocarcinoma was positive for the epidermal growth factor receptor gene mutation exon 21 L858R and had been treated with osimertinib. She presented with multiple bilaterally positioned thin-walled lung cysts and pneumothorax. Lung cysts were diagnosed as cystic lung metastases from lung cancer, and carboplatin, pemetrexed, and pembrolizumab were subsequently administered. All cysts markedly decreased in size, and some disappeared. Conclusion: Effective treatment methods for cystic lung metastases from lung cancer have not been reported. To our knowledge, this is the first case of cystic lung metastases that were successfully treated with chemotherapy.

Successful Treatment of Granulomatous-lymphocytic Interstitial Lung Disease in a Patient with CTLA-4 Deficiency.

Common variable immunodeficiency (CVID) causes granulomatous-lymphocytic interstitial lung disease (GLILD) and has a poor prognosis. We herein report a case of GLILD in a 49-year-old woman with CTLA-4 deficiency-associated CVID. The patient presented with dyspnea that had worsened over the past two years. A laboratory examination revealed hypoglobulinemia and pancytopenia. Chest computed tomography showed diffuse infiltrative and granular shadows in the bilateral interstitium. A flow cytometric analysis of blood cells and genetic testing confirmed CTLA-4 deficiency. We performed video-assisted thoracoscopic surgery for the pathological diagnosis of GLILD and to exclude infection and malignancy. Corticosteroid treatment successfully improved the condition of the patient.

1270 nm near-infrared light as a novel vaccine adjuvant acts on mitochondrial photoreception in intradermal vaccines.

With the development of laser technology in the 1960s, a technique was developed to inject intradermal vaccines immediately after irradiating the skin with laser light to elicit an adjuvant effect, referred to as "laser adjuvant." We have been investigating the mechanism of laser adjuvant in influenza mouse models using noninvasive continuous-wave (CW) near-infrared (NIR) light mainly at a wavelength of 1064 nm, and have shown that the production of reactive-oxygen-species (ROS) in the skin and mast cells in the skin tissue plays an important role in the laser adjuvant effect. The new wavelength of 1270 nm NIR light is characterized by its ability to elicit the same vaccine adjuvant effect as other wavelengths at a lower energy, and may be suitable for clinical applications. In this study, we investigated the physiological activity of CW1270 nm NIR light in mast cells, its biological activity on mouse skin, and the durability of the vaccine adjuvant effect in influenza vaccine mouse models. We show that irradiation of mast cells with 1270 nm NIR light produced ROS and ATP, and irradiation of isolated mitochondria also produced ATP. In mouse skin, the relative expression levels of chemokine mRNAs, such as Ccl2 and Ccl20, were increased by irradiation with 1270 and 1064 nm NIR light at minimum safe irradiance. However, the relative expression of Nfkb1 was increased at 1064 nm, but not at 1270 nm. Serum anti-influenza IgG antibody titers increased early after immunization with 1064 nm, whereas with 1270 nm, there was not only an early response of antibody production but also persistence of antibody titers over the medium- to long-term. Thus, to our knowledge, we show for the first time that 1270 nm NIR light induces ROS and ATP production in mitochondria as photoreceptors, initiating a cascade of laser adjuvant effects for intradermal vaccines. Additionally, we demonstrate that there are wavelength-specific variations in the mechanisms and effects of laser adjuvants. In conclusion, CW1270 nm NIR light is expected to be clinically applicable as a novel laser adjuvant that is equivalent or superior to 1064 nm NIR light, because it can be operated at low energy and has a wavelength-specific adjuvant effect with medium- to long-lasting antibody titer.

Development of intravascular large B-cell lymphoma during prophylactic antibiotic treatment for anti-interferon-gamma autoantibody syndrome: A case report.

Anti-interferon (IFN)-γ autoantibody-positive syndrome is one of the acquired non-HIV cellular immunodeficiencies, caused by abnormalities in the IFN-γ/interleukin (IL)-12 pathways. It is often diagnosed alongside the onset of disseminated mycobacterium infection, and requires continuous antimycobacterial chemotherapy; however, the detailed pathological mechanisms underlying this syndrome, including its prognosis, are not known. To the best of our knowledge, this is the first reported case of intravascular large B-cell lymphoma complicated by anti-IFN-γ autoantibody syndrome, presented in an 82-year-old woman. The patient had been diagnosed with anti-IFN-γ autoantibody immunodeficiency ten years ago. She had repeated subacute fever of undetermined origin for 13 months that made us suspect infections, such as disseminated mycobacterium disease and other viral and fungal infections, despite receiving prophylactic antimycobacterial chemotherapy with rifampicin and clarithromycin. However, all the screenings performed showed no evidence of infectious diseases; thus, she was finally diagnosed with intravascular large B-cell lymphoma via a random skin biopsy. Unfortunately, the patient debilitated rapidly and died. Evidence supporting a correlation between anti-IFN-γ autoantibody syndrome and carcinogenesis is still lacking, although it is known that patients with anti-IFN-γ autoantibody syndrome are at risk of persistent viral infection-related and T-cell lineage-related carcinogenesis. This case demonstrated that patients with anti-IFN-γ autoantibody syndrome are also at risk of developing B-cell lymphoma, such as intravascular lymphoma. This emphasizes that caution should be paid to increased risk of developing malignancy during the long-term management of anti-IFN-γ autoantibody syndrome with cellular immunodeficiency.

Brief exposure of skin to near-infrared laser augments early vaccine responses.

Rapid establishment of herd immunity with vaccination is effective to combat emerging infectious diseases. Although the incorporation of adjuvant and intradermal (ID) injection could augment early responses to the vaccine, the current chemical or biological adjuvants are inappropriate for this purpose with their side effects and high reactogenicity in the skin. Recently, a near-infrared (NIR) laser has been shown to augment the immune response to ID vaccination and could be alternatively used for mass vaccination programs. Here, we determined the effect of NIR laser as well as licensed chemical adjuvants on the immunogenicity 1, 2, and 4 weeks after ID influenza vaccination in mice. The NIR laser adjuvant augmented early antibody responses, while the widely used alum adjuvant induced significantly delayed responses. In addition, the oil-in-water and alum adjuvants, but not the NIR laser, elicited escalated TH2 responses with allergenic immunoglobulin E (IgE) responses. The effect of the NIR laser was significantly suppressed in the basic leucine zipper transcription factor ATF-like 3 (Batf3) knockout mice, suggesting a critical role of the cluster of differentiation 103+ (CD103)+ dendritic cells. The current preliminary study suggests that NIR laser adjuvant is an alternative strategy to chemical and biological agents to timely combat emerging infectious diseases. Moreover, its immunomodulatory property could be used to enhance the efficacy of immunotherapy for allergy and cancer.

Eosinophilic sialoadenitis in a patient with severe asthma: a case report.

Activated eosinophils can infiltrate various tissues and cause inflammatory tissue damage. Asthma is a typical type of eosinophilic inflammatory disease that occurs in the respiratory system. Eosinophilic sialodochitis and sialoadenitis of the salivary gland are rare diseases clinically characterized by painful swelling. In this report, we present a 68-year-old woman with asthma who presented to our hospital with mandibular swelling. Her asthma had been well controlled with an inhaled combination of a corticosteroid and a long-acting ß2 agonist, although she reported a past history of frequent asthma attacks and hospitalization. Laboratory investigation on admission revealed blood eosinophilia (2,673/µL), high levels of total immunoglobulin E (390 U/mL) and immunoglobulin G4 (183 mg/dL). Bone marrow examination showed no evidence of eosinophilic neoplasia. Histological examination of her minor salivary glands disclosed an infiltration of mixed lymphocytes and eosinophils. Chromatolytic eosinophils with Charcot-Leyden crystals were also observed within the edematous dermis and fibrous tissues surrounding the minor salivary gland. The patient was diagnosed with eosinophilic sialoadenitis. Treatment with oral corticosteroids (0.5 mg/kg/day) was initiated. Thereafter, the mandibular swelling improved. This report describes a rare case of eosinophilic sialoadenitis in a patient with severe eosinophilic asthma, for which histopathological and immunefluorescence microscopic analyses were performed.

Medicine at mass gatherings: current progress of preparedness of emergency medical services and disaster medical response during 2020 Tokyo Olympic and Paralympic Games from the perspective of the Academic Consortium (AC2020).

Mass gatherings are events characterized by "the concentration of people at a specific location for a specific purpose over a set period of time that have the potential to strain the planning and response resources of the host country or community." Previous reports showed that, as a result of the concentration of people in the limited area, injury and illness occurred due to several factors. The response plan should aim to provide timely medical care to the patients and to reduce the burden on emergency hospitals, and to maintain a daily emergency medical services system for residents of the local area. Although a mass gathering event will place a significant burden on the local health-care system, it can provide the opportunity for long-term benefits of public health-care and improvement of daily medical service systems after the end of the event. The next Olympic and Paralympic Games will be held in Tokyo, during which mass gatherings will occur on a daily basis in the context of the coronavirus disease (COVID-19) epidemic. The Academic Consortium on Emergency Medical Services and Disaster Medical Response Plan during the Tokyo Olympic and Paralympic Games in 2020 (AC2020) was launched 2016, consisting of 28 academic societies in Japan, it has released statements based on assessments of medical risk and publishing guidelines and manuals on its website. This paper outlines the issues and countermeasures for emergency and disaster medical care related to the holding of this big event, focusing on the activities of the academic consortium.

Zosteriform skin metastasis caused by retrograde lymphatic migration of metastatic squamous cell lung carcinoma.

BACKGROUND: Zosteriform skin metastasis (ZSM) is rare, and its etiology is not well understood. ZSM is possibly derived from the retrograde movement of cancer cells through the lymphatic vessels during disease development. However, it has been difficult to demonstrate it, as no specific findings have been observed. CASE PRESENTATION: A 68-year-old man presented to our department with neck lymphadenopathy. After detailed examinations, squamous cell lung carcinoma (cT2aN3M1c) was diagnosed. Although cisplatin combined with gemcitabine was administered, his cancerous lymphangiopathy was exacerbated, and ZSM was observed on his right chest. Pembrolizumab was initiated as a second-line chemotherapy; however, the patient died 7 months after the initial presentation. In this case, fluorodeoxyglucose-positron emission tomography indicated the presence of skin metastasis and cancerous lymphangiopathy. Similarly, after performing an autopsy, tumor-cell filled lymph ducts were observed in the right subclavian and the cutaneous lymphatic vessel from the right hilar lymph nodes. CONCLUSIONS: To the best of our knowledge, this is the first study to demonstrate that the localization of ZSM in the cutaneous lymphatics was caused by the retrograde movement of cancer cells through the lymphatic vessels, using radiographical and pathological analysis. In addition, fluorodeoxyglucose-positron emission tomography may help predict skin metastasis induced by cancerous lymphangiopathy.

Lung adenocarcinoma with repetitive endotracheal/endobronchial metastasis 20 years after surgery: A case report.

The occurrence of endotracheal/endobronchial metastasis (EEM) after complete resection of a primary lung cancer is rare. Here, we report the case of an 86-year-old woman in whom EEM occurred twice over a 20-year period following complete resection of a primary adenocarcinoma localized to the left main bronchus and trachea. The presence of EEM was confirmed by establishing immunohistochemical homology of the metastases with the primary tumor. To the best of our knowledge, this is the first reported case of repetitive EEM of primary lung adenocarcinoma. Lymphatic invasion in the primary lesion suggested that a possible route for EEM was the peripheral lymphatic tract, explaining the slow recurrence rate. We conclude that observation of the trachea/bronchus over a long period post operation could be important in monitoring for EEM, particularly if lymphatic invasion is confirmed in the primary tumor.

Serum surfactant protein A as a surrogate biomarker of a negative heart sign among patients with interstitial lung disease.

The mechanisms underlying interstitial lung disease (ILD) are characterized by variable inflammation or fibrosis of the pulmonary interstitium. A negative heart sign (NHS) on 67Ga scintigrams of patients with ILD is due to considerably increased inflammatory activity in the lungs. We retrospectively analyzed relationships between NHS and established biomarkers of disease severity in patients with ILD. Among 81 consecutive non-smoking patients with ILD (mean age, 63 years) who had been hospitalized between April 2009 and October 2011, we selected 52 who had been assessed by 67Ga scintigraphy. We then evaluated relationships between NHS and blood biomarkers, pulmonary function and high-resolution computed tomography (HRCT). Among these 52 patients, 10 showed idiopathic pulmonary fibrosis and 42 had other ILD. Multivariate analysis with stepwise variable selection, serum surfactant protein (SP)-A (OR (odds ratio), 1.026; 95%CI (confidence interval), 1.003-1.050; P = 0.024) and inflammation index calculated from HRCT findings (OR, 1.358; 95%CI, 1.079-1.709; P = 0.009) were significant predictors of an NHS. Serum SP-A offered 85% sensitivity and 75% specificity for predicting NHS at an optimal cut-off of 45.8 ng/mL. Serum SP-A concentrations correlated positively with inflammation index (r = 0.344, P = 0.015). In conclusion, serum SP-A might serve as a surrogate biomarker for predicting an NHS in patients with ILD.

Serum soluble interleukin-2 receptor level is a predictive marker for EBUS-TBNA-based diagnosis of sarcoidosis.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widely available diagnostic tool for suspected stage I/II sarcoidosis. Combination of EBUS-TBNA and transbronchial lung biopsy (TBLB) has been proposed as diagnostic procedure in clinical settings. OBJECTIVES: The aim of this study was to assess the diagnostic yield of combined EBUS-TBNA and TBLB and identify the markers correlated with a high diagnostic rate. METHODS: We retrospectively analyzed the data of 37 patients with suspected stage I/II sarcoidosis with enlarged hilar or mediastinal lymph nodes on computed tomography (CT) images. These patients had been scheduled to undergo EBUS-TBNA and TBLB. Serum levels of sarcoidosis markers (angiotensin-converting enzyme [ACE], soluble interleukin-2 receptor [sIL-2R], and lysozyme), CT findings, and examination techniques were evaluated as predictive markers for diagnosis. RESULTS: Of the 37 patients, 32 had undergone both EBUS-TBNA and TBLB, while the remaining 5 patients had only undergone EBUS-TBNA. The diagnosis was confirmed by TBLB in 16 of the 32 patients (50.0%), EBUS-TBNA in 31 of the 37 patients (83.8%), and combined TBLB and EBUS-TBNA in all patients (100.0%). The serum level of sIL-2R, but not that of ACE or lysozyme, was correlated with successful diagnosis by EBUS-TBNA. CONCLUSION: In patients with stage I/II sarcoidosis, the serum level of sIL-2R is a promising and useful marker for predicting the diagnosis by EBUS-TBNA and reducing the burden of additional TBLB and its possible complications. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 8-16).

Dysregulated metabolism of polyunsaturated fatty acids in eosinophilic allergic diseases.

Polyunsaturated fatty acids (PUFAs), represented by the omega-6 fatty acid arachidonic acid (AA) and omega-3 fatty acid docosahexaenoic acid (DHA), are essential components of the human body. PUFAs are converted enzymatically into bioactive lipid mediators, including AA-derived cysteinyl leukotrienes (cys-LTs) and lipoxins and DHA-derived protectins, which orchestrate a wide range of immunological responses. For instance, eosinophils possess the biosynthetic capacity of various lipid mediators through multiple enzymes, including 5-lipoxygenase and 15-lipoxygenase, and play central roles in the regulation of allergic diseases. Dysregulated metabolism of PUFAs is reported, especially in severe asthma, aspirin-exacerbated respiratory disease, and eosinophilic chronic rhinosinusitis (ECRS), which is characterized by the overproduction of cys-LTs and impaired synthesis of pro-resolving mediators. Recently, by performing a multi-omics analysis (lipidomics, proteomics, and transcriptomics), we demonstrated the metabolic derangement of eosinophils in inflamed tissues of patients with ECRS. This abnormality occurred subsequent to altered enzyme expression of gamma-glutamyl transferase-5. In this review, we summarize the previous findings of dysregulated PUFA metabolism in allergic diseases, and discuss future prospective therapeutic strategies for correcting this imbalance.

Pazopanib-induced organizing pneumonia in a patient with leiomyosarcoma: A case report.

Pazopanib, a multityrosine kinase inhibitor used for treating malignant soft tissue tumors, rarely causes adverse events associated with the respiratory system. We report a case of a 73-year-old male with leiomyosarcoma treated with pazopanib. Four months after treatment initiation, chest computed tomography showed bilateral patchy consolidation and ground-glass opacities. Bronchoscopy revealed increased lymphocytes in the bronchoalveolar lavage fluid. Histological analysis of lung tissue demonstrated intraluminal fibrotic changes in alveolar spaces. According to these findings, we diagnosed the patient with pazopanib-induced organizing pneumonia. To best of our knowledge, this is the first report of such a case.

Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review.

Hypercalcemia of malignancy frequently manifests as paraneoplastic syndrome in patients with solid tumors. A 71-year-old man was diagnosed with stage IIIB lung squamous cell carcinoma. Laboratory examination revealed high serum calcium concentration with elevated serum parathyroid hormone-related protein (PTHrP) and 1,25-dihydroxyvitamin D3 levels. As the patient did not respond to the initial treatment with calcitonin, extracellular fluid infusion, and chemotherapy, systemic prednisolone was administered additionally. Thus, the levels of serum calcium normalized and PTHrP and 1,25-dihydroxyvitamin D3 decreased simultaneously. To our knowledge, this is the first case report on the successful treatment of hypercalcemia of malignancy caused by PTHrP and 1,25-dihydroxyvitamin D3 cosecretion in a patient with lung cancer.