Impact of Plasma 5 Hydroxyindoleacetic Acid, a Serotonin Metabolite, on Clinical Severity in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated vascular permeability. The clinical outcomes remain poor, and the disease burden is widespread. We demonstrated that plasma 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, is a pivotal severity indicator of ARDS. Serotonin is an effector of cellular contraction and a modulator of vascular permeability. Plasma 5-HIAA levels were significantly elevated in severe ARDS cases with shock status (p = 0.047) and positively correlated with SOFA (p < 0.0001) and APACHE-II score (p < 0.0001). In the longitudinal analysis, plasma 5-HIAA levels were also a strong independent predictor of mortality rate (p = 0.005). This study indicates that plasma 5-HIAA is a biomarker of ARDS severity and highlights the importance of evaluating vascular leakage levels for ARDS treatment

Impaired Anaphylactic Responses with Intact Sensitivity to Endotoxin in Mice Lacking a Platelet-activating Factor Receptor

Platelet-activating factor (PAF) is a potent phospholipid mediator with diverse biological activities in addition to its well-known ability to stimulate platelet aggregation. Pharmacologic studies had suggested a role for PAF in pregnancy, neuronal cell migration, anaphylaxis, and endotoxic shock. Here we show that disruption of the PAF receptor gene in mice caused a marked reduction in systemic anaphylactic symptoms. Unexpectedly, however, the PAF receptor–deficient mice developed normally, were fertile, and remained sensitive to bacterial endotoxin. These mutant mice clearly show that PAF plays a dominant role in eliciting anaphylaxis, but that it is not essential for reproduction, brain development, or endotoxic shock

Clinical and microbiological characteristics and challenges in diagnosing infected aneurysm: a retrospective observational study from a single center in Japan

Background: It is challenging to diagnose infected aneurysm in the early phase. This study aimed to describe the clinical and microbiological characteristics of infected aneurysm, and to elucidate the difculties in diagnosing the disease.Methods: Forty-one cases of infected aneurysm were diagnosed in Nagasaki University Hospital from 2005 to 2019. Information on clinical and microbiological characteristics, radiological fndings, duration of onset, and type of initial computed tomography (CT) imaging conditions were collected. Factors related to diagnostic delay were analyzed by Fisher’s exact test for categorical variables or by the Wilcoxon rank-sum test for continuous variables.Results: Pathogens were identifed in 34 of 41 cases; the pathogens were Gram-positive cocci in 16 cases, Gram-negative rods in 13 cases, and others in fve cases. Clinical characteristics did not difer in accordance with the identifed bacteria. At the time of admission, 16 patients were given diferent initial diagnoses, of which acute pyelonephritis (n=5) was the most frequent. Compared with the 22 patients with an accurate initial diagnosis, the 19 initially misdiagnosed patients were more likely to have been examined by plain CT. The sensitivities of plain CT and contrastenhanced CT were 38.1% and 80.0%, respectively.Conclusions: In cases of infected aneurysm, diagnostic delay is attributed to non-specifc symptoms and the low sensitivity of plain CT. Clinical characteristics of infected aneurysm mimic various diseases. Contrast-enhanced CT should be considered if infected aneurysm is suspected

Association between potassium supplementation and the occurrence of acute kidney injury in patients with hypokalemia administered liposomal amphotericin B: a nationwide observational study

Background: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood.Methods: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation.Results: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584–2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400–2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358).Conclusion: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB

Efficacy of early administration of liposomal amphotericin B in patients with septic shock: A nationwide observational study

Introduction: Liposomal amphotericin B (L-AMB), a broad spectrum anti-fungicidal drug, is often administered to treat invasive fungal infections (IFIs). However, the most suitable time to initiate treatment in septic shock patients with IFI is unknown.Methods: Patients with septic shock treated with L-AMB were identified from the Japanese Diagnosis Procedure Combination national database and were stratified according to L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) to determine their survival rates following septic shock onset and the shock cessation period.Results: We identified 141 patients administered L-AMB on the day of or after septic shock onset: 60 patients received early treatment, whereas 81 patients received delayed treatment. Survival rates after septic shock onset were higher in the early L-AMB group than in the delayed L-AMB group (4 weeks: 68.4% vs 57.9%, P = 0.197; 6 weeks: 62.2% vs 44.5%, P = 0.061; 12 weeks: 43.4% vs 35.0%, P = 0.168, respectively). The septic shock cessation period was shorter in the early L-AMB group than in the delayed L-AMB group (7.0 ± 7.0 days vs 16.5 ± 15.4 days, P < 0.001), with a significant difference confirmed after adjusting for confounding factors with propensity score matching (7.1 ± 7.2 days vs 16.7 ± 14.0 days, P = 0.001).Conclusion: Early L-AMB administration at septic shock onset may be associated with early shock cessation

Nationwide surveillance of AIDS-defining illnesses among HIV patients in Japan from 1995 to 2017

Objectives: The accurate prevalence of acquired immunodeficiency syndrome (AIDS)-defining illnesses (ADIs) in human immunodeficiency virus (HIV)-infected patients has not been well investigated. Hence, a longitudinal nationwide surveillance study analyzing the current status and national trend of opportunistic complications in HIV-infected patients in Japan is warranted.Methods: A nationwide surveillance of opportunistic complications in HIV-infected patients from 1995 to 2017 in Japan was conducted. An annual questionnaire was sent to 383 HIV/AIDS referral hospitals across Japan to collect information (CD4+ lymphocyte count, time of onset, outcome, and antiretroviral therapy [ART] status) of patients diagnosed with any of 23 ADIs between 1995 and 2017.Results: The response and case capture rates of the questionnaires in 2017 were 53% and 76%, respectively. The number of reported cases of opportunistic complications peaked in 2011 and subsequently declined. Pneumocystis pneumonia (38.7%), cytomegalovirus infection (13.6%), and candidiasis (12.8%) were associated with the cumulative incidence of ADIs between 1995 and 2017. The mortality rate in HIV-infected patients with opportunistic complications substantially decreased to 3.6% in 2017. The mortality rate was significantly higher in HIV patients who received ART within 14 days of diagnosis of complications than in those who received ART 15 days after diagnosis (13.0% vs. 3.2%, p < 0.01).Conclusions: We have demonstrated a 23-year trend of a newly diagnosed AIDS status in Japan with high accuracy. The current data reveal the importance of Pneumocystis pneumonia as a first-onset illness and that early initiation of ART results in poor outcomes in HIV patients in Japan

Pathogenesis and clinical features of chronic pulmonary aspergillosis ? Is it possible to distinguish CNPA and CCPA clinically?

Background: The pathogenesis of chronic pulmonary aspergillosis (CPA) including chronic necrotizing pulmonary aspergillosis (CNPA), chronic cavitary pulmonary aspergillosis (CCPA), and simple aspergilloma (SA) has been poorly investigated. We examined all types of CPA cases with histopathological evidence to clarify the differences in pathogenesis and clinical features. Method: We searched for cases diagnosed as pulmonary aspergillosis by histopathological examination in Nagasaki University Hospital between 1964 and September 2010. All available clinical information including radiological findings were collected and analyzed. Result: We found 7, 5, 8, and 7 cases of proven CNPA, probable CNPA, CCPA, and SA, respectively. The radiograph of proven and probable CNPA was initially infiltrates or nodules that progress to form cavities with or without aspergilloma, whereas the radiograph of CCPA showed pre-existed cavities and pericavitary infiltrates with or without aspergilloma. The patients with proven and probable CNPA exhibited not only respiratory symptoms but also systemic symptoms and malnutrition. Aspergillus fumigatus was the most frequently isolated Aspergillus species (n = 14), however, Aspergillus niger was the predominant isolated species in proven CNPA cases (n = 4). Conclusion: Our data indicate that the cases with chronic infiltration, progressive cavitation, and subsequent aspergilloma formation should be diagnosed as CNPA, and the cases with pre-existed cavities showing peri-cavitary infiltrates with or without aspergilloma would mean CCPA. However, it may be difficult to distinguish the two subtypes if a series of adequate radiography films are not available. We propose the term "chronic progressive pulmonary aspergillosis (CPPA)" for the clinical syndrome including both CNPA and CCPA

Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability

Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability