Validation of a diagnostic flowchart for tuberculous pleurisy in pleural fluid with high levels of adenosine deaminase.

INTRODUCTION: Adenosine deaminase (ADA) in pleural fluid is a useful marker for diagnosing tuberculous pleurisy. However, recent studies have reported a lower specificity of pleural fluid ADA levels. We previously developed a diagnostic flowchart for patients with pleural fluid ADA ≥40 U/L, incorporating variables such as pleural fluid lactate dehydrogenase <825 U/L, predominant pleural fluid neutrophils or cell degeneration, and a pleural fluid ADA/total protein ratio <14. This flowchart was effective in distinguishing between tuberculous pleurisy and other diseases. Here, we conducted a validation analysis of this flowchart. MATERIALS AND METHODS: We retrospectively collected data from 458 patients with pleural fluid ADA concentrations ≥40 U/L across eight institutions from January 2019 to December 2023. The diagnostic accuracy rate, sensitivity, and specificity of the diagnostic flowchart were analysed and compared to those in the original study. RESULTS: Eighty-seven patients were diagnosed with tuberculous pleurisy, and 371 patients were diagnosed with other diseases. The diagnostic accuracy, sensitivity, and specificity for diagnosing tuberculous pleurisy were 77.7%, 86.2%, and 75.7%, respectively. Compared with that in the original study, the rate of tuberculous pleurisy was lower (19.0% vs. 44.5%, p < 0.001), but the diagnostic accuracy rates were not significantly different (p = 0.253). On the basis of the findings from this validation study, we have revised the flowchart to enhance its utility. CONCLUSION: The diagnostic flowchart exhibited high diagnostic accuracy in this validation study, comparable to that in the original study. This validation confirms the effectiveness of the flowchart, even in settings with a low incidence of tuberculosis.

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.

Splenic Infarction Associated With Epstein-Barr Virus in an Adult With an Anatomic Anomaly: A Case Report.

Splenic infarction (SI) is often associated with circulatory and hematological diseases and infections. Here, we report a rare case of SI in an adult with infectious mononucleosis (IM) caused by the Epstein-Barr (EB) virus. A 31-year-old male with an unremarkable medical history presented with abdominal pain and fever. Contrast-enhanced computed tomography revealed focal SI. The splenic artery branching from the superior mesenteric artery was <5 mm in diameter. The diagnosis of EB virus infection was made based on physical examination and blood test results. As no evidence of cardiogenic disease, malignant lymphoma, or other infections were present, a diagnosis of SI associated with IM was made. A symptomatic treatment was administered, and the splenomegaly and SI improved two weeks after discharge. IM was assumed as the cause of the focal SI.

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.

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.

Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease.

BACKGROUND AND OBJECTIVE: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. METHODS: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). RESULTS: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. CONCLUSION: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

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.

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 Control of Dasatinib-related Chylothorax by the Japanese Herbal Medicine "Goreisan".

Dasatinib-related chylothorax is a rare adverse event, and the mechanism underlying its occurrence is still not fully understood. We herein report the case of a 73-year-old woman with chronic myeloid leukemia (CML) who developed dasatinib-related chylothorax refractory to conventional treatments, except for steroids. To the best of our knowledge, this is the first case of dasatinib-related chylothorax which was successfully controlled by combining diuretics with the Japanese herbal medicine "Goreisan." "Goreisan" is known to inhibit aquaporin channels and regulate the water flow. Our findings showed that "Goreisan" is an effective treatment option for uncontrollable dasatinib-related chylothorax.

Development of Allergic Bronchopulmonary Aspergillosis in a Patient with Crohn's Disease.

Allergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic inflammatory condition characterized by exaggerated immune responses to the fungal genus Aspergillus. Pulmonary manifestations in patients with Crohn's disease (CD) are frequent comorbidities. A 66-year-old man with CD treated with an anti-tumor necrosis factor-α antibody presented with dyspnea. Laboratory findings of elevated blood eosinophils and total serum IgE and positive aspergillus-specific antibodies as well as imaging findings of central bronchiectasis and mucoid impaction indicated a diagnosis of ABPA. To our knowledge, this is the first report of ABPA arising in a patient with CD. We discuss the pathophysiological mechanism of this rare complication.

Brief Exposure of Skin to Near-Infrared Laser Modulates Mast Cell Function and Augments the Immune Response.

The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases.

CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis.

Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2(-/-)) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2(-/-) mice, blunting CLP-induced lethality in CRTH2(-/-) mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2(-/-) mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2(-/-) mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.