A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

Peripherally inserted central venous catheters decrease central line-associated bloodstream infections and change microbiological epidemiology in adult hematology unit: a propensity score-adjusted analysis.

Peripherally inserted central venous catheters (PICCs) have a potential advantage in preventing central line-associated bloodstream infection (CLABSI) compared with the centrally inserted ones (CICCs). However, due to a limited number of studies with insufficient statistical evaluation, the superiority of PICCs is difficult to be generalized in adult hematology unit. We conducted a single-center retrospective study and compared the risk of CLABSI between 472 CICCs and 557 PICCs inserted in adult patients with hematological disorders through conventional multivariate models and a propensity score-adjusted analysis. The overall CLABSI incidence in CICCs and PICCs was 5.11 and 3.29 per 1000 catheter days (P = 0.024). The multivariate Cox regression analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.31-0.75; P = 0.001) and Fine-Gray subdistribution analysis (HR: 0.59; 95% CI: 0.37-0.93; P = 0.023) demonstrated that PICC was independently associated with a reduced risk of CLABSI. Moreover, the stabilized inverse probability of treatment weighting analysis, which further reduced the selection bias between CICCs and PICCs, showed that PICCs significantly prevented CLABSI (HR: 0.58; 95% CI: 0.35-0.94; P = 0.029). Microbiologically, PICCs showed a significant decrease in gram-positive cocci (P = 0.001) and an increase in gram-positive bacilli (P = 0.002) because of a remarkable reduction in Staphylococci and increase in Corynebacterium species responsible for CLABSI. Our study confirmed that PICC was a superior alternative to CICC in preventing CLABSI in the adult hematology unit, while it posed a microbiological shift in local epidemiology.

Protein-losing enteropathy caused by disseminated Mycobacterium avium complex infection in a patient receiving antiretroviral therapy: an autopsy case report.

BACKGROUND: Disseminated Mycobacterium avium complex infection is an important indicator of acquired immunodeficiency syndrome (AIDS) in patients with advanced human immunodeficiency virus (HIV) infection. Effective antiretroviral therapy has dramatically reduced the incidence of and mortality due to HIV infection, although drug resistance and poor medication adherence continue to increase the risk of disseminated M. avium complex infection. However, gastrointestinal lesions in cases of disseminated M. avium complex infection resulting in protein-losing enteropathy have been rarely discussed. Therefore, we present a case of protein-losing enteropathy caused by disseminated M. avium complex infection in a patient undergoing antiretroviral therapy. CASE PRESENTATION: A 29-year-old man was diagnosed with AIDS 4 years ago and was admitted for a 10-month history of refractory diarrhea and fever. Despite receiving antiretroviral therapy, the viral load remained elevated due to poor medication adherence. The patient was diagnosed with disseminated M. avium complex infection and started on antimycobacterial drugs 2 years before admission. However, the infection remained uncontrolled. The previous hospitalization 1 year before admission was due to hypoalbuminemia and refractory diarrhea. Upper gastrointestinal endoscopy revealed a diagnosis of protein-losing enteropathy caused by intestinal lymphangiectasia, and treatment with intravenous antimycobacterial drugs did not resolve his intestinal lymphangiectasia. The patient inevitably died of sepsis. CONCLUSIONS: Clinical remission is difficult to achieve in patients with AIDS and protein-losing enteropathy caused by disseminated M. avium complex infection due to limited options of parenteral antiretroviral drugs. This report highlights the importance of identifying alternative treatments (such as an injectable formulation) for patients who do not respond to antiretroviral therapy due to protein-losing enteropathy with disseminated M. avium complex infection.

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data.

INTRODUCTION: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. METHODS: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. RESULTS: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. CONCLUSIONS: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

Dengue Virus Type 1 Infection in Traveler Returning from Tanzania to Japan, 2019.

The largest outbreak of dengue fever in Tanzania is ongoing. Dengue virus type 1 was diagnosed in a traveler who returned from Tanzania to Japan. In phylogenetic analysis, the detected strain was close to the Singapore 2015 strain, providing a valuable clue for investigating the dengue outbreak in Tanzania.

Comparison between procalcitonin and C-reactive protein in predicting bacteremias and confounding factors: a case-control study.

BACKGROUND: The detection of infectious bacteria in blood culture samples is important for diagnosis and treatment, but this requires 1-2 days at least, and is not adequate as a rapid test. Therefore, we have investigated the diagnostic ability and the optimal cutoff value of procalcitonin (PCT) and C-reactive protein (CRP) for predicting the bacteremias using receiver operating characteristic (ROC) curves and relative cumulative frequency distribution (RCD) curves. METHODS: A case-control study was performed in inpatients (852 subjects: 426 positive cultures and 426 negative cultures) from January 1 to December 31, 2014. We retrospectively investigated their blood culture and blood chemistry findings recorded in this period using electronic medical records. RESULTS: Area under the ROC curve of PCT and CRP were 0.79 and 0.66, respectively. The optimal cutoff values were 0.5 µg/L with a sensitivity of 70% and specificity of 70% for PCT and 50.0 mg/L with a sensitivity of 63% and specificity of 65% for CRP. When the optimal cutoff value was treated as a reference, the odds ratio (OR) was 71.11 and the hazard ratio (HR) was 6.27 for PCT >2.0 µg/L, and the risk of blood culture positivity was markedly elevated. PCT levels were significantly higher in the population with Gram-negative rod (GNR) infections than in the population with Gram-positive coccal (GPC) infections. CONCLUSIONS: The elevation of CRP and PCT were significantly associated with bacteremias. PCT was superior to CRP as a diagnostic indicator for predicting bacteremias, for discriminating bacterial from nonbacterial infections, and for determining bacterial species.

Dengue virus type 3 infection in a traveler returning from Costa Rica to Japan in 2023.

The number of dengue cases has increased dramatically in recent years. In Latin America, the number of cases and deaths in 2023 was the highest ever recorded. We report on a patient who had been infected with dengue virus during his stay in Costa Rica in September 2023, and developed the disease after returning to Japan. Plasma obtained from the patient was used for diagnosis and dengue virus serotyping by real-time PCR. The nucleotide sequence of the envelope region of dengue virus was then determined by the direct sequencing method, and this sequence was used for phylogenetic analyses. The patient was found to be infected with dengue virus type 3 genotype III. The sequence from the present case was more homologous with sequences registered in Florida, USA, associated with travel to Cuba in 2022 than with sequences registered in Costa Rica 10 years ago. The Pan American Health Organization reported that only dengue virus type 1 and 2 cases were reported in Costa Rica in 2019-2021, whereas dengue virus type 3 and 4 cases started being reported in 2022. In 2023, the reported numbers of cases with dengue virus types 3 and 4 exceeded those of dengue virus types 1 and 2. In addition, regional differences in endemic strains have been observed in Costa Rica. Our findings suggest that the dengue virus type 3 that infected the patient was more likely an influx of a strain that had been circulating in Caribbean countries such as Cuba in recent years, rather than a re-emergence of an indigenous virus in Costa Rica. The serotypes of dengue virus prevalent in Costa Rica have been changing since 2022. All four serotypes were prevalent in 2023, with a particularly sharp increase in the number of cases of dengue virus types 3 and 4. Future monitoring and surveillance are essential because changes in endemic serotypes can cause antibody-dependent enhancement, which can lead to severe dengue disease presentations.

Travel-associated sexually transmitted infections in Japan: An observational study using imported infectious disease registry data.

International travel is a risk factor for acquiring sexually transmitted infections (STIs) owing to factors such as increased sexual opportunities, a sense of freedom, and the allure of the sex industry. We investigated the incidence of travel-associated STIs in Japan using data from the Japan Registry for Infectious Diseases from Abroad (J-RIDA) reported by 17 participating medical institutions between October 2017 and December 2022. Data were collected on the patients' age, sex, nationality, chief complaint, whether they had visited a travel clinic before travel, travel history, and final diagnosis. Of 4545 cases of travel-associated illness reported, 52 (1.1%) were STIs. Most patients with STIs were male (81%) with a median age of 31 years. HIV (17%), genital herpes (13%), syphilis (13%), and gonorrhea (12%) were the most frequently reported STIs. Only one patient had visited a travel clinic before travel. Promoting awareness and vaccination is crucial for preventing travel-associated STIs.

Life-threatening pneumothorax after release from isolation with COVID-19 pneumonia.

Pneumothorax was previously considered as a complication of severe coronavirus disease 2019 (COVID-19) pneumonia. However, it is now known that pneumothorax can develop in other cases. Here, we describe the case of a patient who developed tension pneumothorax after release from isolation from COVID-19 pneumonia. The patient was admitted to our hospital with severe COVID-19 pneumonia on the 10th day after onset. Ventilatory management was carried out on the first day of admission; however, the patient was weaned off the next day. The treatment course was uneventful. On the morning of discharge from the hospital, the patient experienced sudden dyspnea. Chest radiography revealed a large left-tension pneumothorax with a mediastinal shift to the right. As this finding required immediate attention, a chest tube was inserted. Chest computed tomography (CT) showed an airspace in the left thoracic cavity and subpleural thin-walled cystic lesions, such as bullae in the left lobe. One month later, chest CT showed resolution of the cystic lesions. The development of pneumothorax in COVID-19 pneumonia should be considered not only in cases of severe illness, but also after release from isolation. Recently, revisions to measures against COVID-19 have been considered worldwide, including shortening of the isolation period and reviewing the identification of all cases. This is an educational report demonstrating that life-threatening pneumothorax may develop after release from isolation due to COVID-19 pneumonia.

Evaluation of potential rabies exposure among Japanese international travelers: A retrospective descriptive study.

BACKGROUND: Although Japan has been a rabies-free country for >50 years, a few cases have been reported among people traveling abroad. This study aimed to investigate animal exposure among Japanese travelers using the Japanese Registry for Infectious Diseases from Abroad (J-RIDA). METHOD: In this retrospective analysis, we examined Japanese overseas travelers with animal exposure, as included the J-RIDA database, reported from October 1, 2017, to October 31, 2019, with a focus on pre-exposure prophylaxis (PrEP) administration and the animals to which the patients were exposed. RESULTS: Among the 322 cases included in the analysis, 19 (5.9%) patients received PrEP and 303 did not. The most common purpose of travel was a non-package tour (n = 175, 54.3%). Most trips (n = 213, 66.1%) were to a single country for <2 weeks. Most patients (n = 286, 87.9%) traveled to countries with a rabies risk. The majority of patients with and without PrEP were injured in rabies-risk countries [n = 270 (89.1%) for non-PrEP and n = 16 (84.2%) for PrEP]. Animals associated with injuries included dogs (55.0%), cats (25.5%), and monkeys (15.5%). Most patients were classified as World Health Organization Category II/III for contact with suspected rabid animals (39.5% and 44.1% for categories II and III, respectively) and had exposure within 5 days of travel. Southeast Asia (n = 180, 55.9%) was the most common region in which travelers were exposed to animals. CONCLUSIONS: Japanese overseas travelers had contact with animals that could possibly transmit the rabies virus, even on short trips. Promoting pre-travel consultation and increasing awareness of the potential for rabies exposure are important for prevention of rabies among Japanese international travelers.

Epidemiological trends of traveler's diarrhea in Japan: An analysis of imported infectious disease registry data from 2017-2022.

Traveler's diarrhea (TD) is a global problem, and identifying the causative organisms of TD is important for adequate treatment. Therefore, this study retrospectively analyzed TD cases in patients who returned to Japan after traveling abroad to determine the causative organisms by travel region. We included patients with a final diagnosis of TD registered in the Japan Registry for Infectious Diseases from Abroad database from September 25, 2017, to September 1, 2022, from 14 medical institutions. A total of 919 patients were analyzed; the causative TD pathogen was identified in 188 cases (20%), of which 154 were caused by diarrheagenic bacteria, the most common being Campylobacter spp. (64%). A 2.2 mg/dL C-reactive protein concentration cutoff value had some predictive ability for bacterial TD (negative predictive value, 89%). Therefore, the C-reactive protein level may help rule out bacterial diarrhea and prevent unnecessary antimicrobial administration when patients cannot provide a stool specimen.

COVID-19 relapse associated with SARS-CoV-2 evasion from CD4+ T-cell recognition in an agammaglobulinemia patient.

A 25-year-old patient with a primary immunodeficiency lacking immunoglobulin production experienced a relapse after a 239-day period of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral genetic sequencing demonstrated that SARS-CoV-2 had evolved during the infection period, with at least five mutations associated with host cellular immune recognition. Among them, the T32I mutation in ORF3a was found to evade recognition by CD4+ T cells. The virus found after relapse showed an increased proliferative capacity in vitro. SARS-CoV-2 may have evolved to evade recognition by CD4+ T cells and increased in its proliferative capacity during the persistent infection, likely leading to relapse. These mutations may further affect viral clearance in hosts with similar types of human leukocyte antigens. The early elimination of SARS-CoV-2 in immunocompromised patients is therefore important not only to improve the condition of patients but also to prevent the emergence of mutants that threaten public health.

[Enterohemorrhagic E. coli (EHEC)].

Escherichia coli (E. coli) is a bacterium that is commonly found in the gut of humans and warm-blooded animals. Most strains of E. coli are harmless. Some strains however, such as enterohemorrhagic E. coli (EHEC), can cause severe foodborne disease. It is transmitted to humans primarily through consumption of contaminated foods, such as raw meal. EHEC produces toxins, known as verotoxins. EHEC that induces bloody diarrhea leads to HUS in 10% of cases. The clinical manifestations of post-diarrheal HUS include acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. The verocytotoxin can directly damage renal and endothelial cells. Thrombocytopenia occurs as platelets are consumed by clotting. Hemolytic anemia results from intravascular fibrin deposition, increased fragility of red blood cells, and fragmentation.

Sarcopenia among people living with HIV and the effect of antiretroviral therapy on body composition.

To investigate the prevalence of sarcopenia among people living with HIV (PLWH) in Japan and analyze the relationship between HIV infection and ART effects on the body composition of Japanese PLWH for more appropriate drug selection and lifestyle guidance. Cross-sectional observational study. We included male patients aged ≥ 60 years whose body composition was measured by InBody 570 body composition analyzer during outpatient visits. Patients were classified by body shape based on body mass index (BMI) and body fat percentage measurements and by tenofovir alafenamide administration. Hidden obesity is a condition wherein the BMI is within the standard range but the body fat percentage is higher than the reference. Patients with low muscle mass and strength were considered to have sarcopenia, whereas those with only low muscle strength were considered to have pre-sarcopenia. In total, 87 patients were included. Based on body shape determined by BMI and body fat percentage, most patients had hidden obesity (40 patients, 46.0%). Sarcopenia was detected in 9 patients (10.3%) and pre-sarcopenia in 14 patients (16.1%). The tenofovir alafenamide (TAF) use group had significantly higher BMI, higher skeletal muscle mass, body fat mass, and skeletal muscle mass index relative to the non-TAF use group. Hidden obesity is a risk for lifestyle diseases. It is important to recognize it based on body composition measurements because it can be missed by BMI measurement alone. Tenofovir alafenamide therapy increases skeletal muscle mass, which may result in the prevention of sarcopenia. To clarify how TAF affects the development of sarcopenia and lifestyle diseases, future studies on a larger cohort are warranted.

A case of Schistosoma japonicum retroperitoneal pseudotumor diagnosed by cone-beam CT-guided coaxial biopsy system.

We report a rare case of retroperitoneal pseudotumor caused by Schistosoma japonicum that was diagnosed by computed tomography (CT) guided percutaneous biopsy in a 15-year-old Filipino male. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a mass lesion, including a mesenteric artery, in the right retroperitoneal space. His mother had a history of S. japonicum infection but his initial stool examination was negative. As schistosomiasis was suspected, cone-beam CT-guided biopsy was performed to enable transcatheter therapeutic arterial embolization to be performed immediately in the event of hemorrhage. Histopathological examination revealed schistosomal eggs. Cone-beam CT-guided technique with a coaxial biopsy system is a safe and accurate diagnostic procedure for S. japonicum retroperitoneal pseudotumor.

Integrated model for COVID-19 diagnosis based on computed tomography artificial intelligence, and clinical features: a multicenter cohort study.

Background: We developed and validated a machine learning diagnostic model for the novel coronavirus (COVID-19) disease, integrating artificial-intelligence-based computed tomography (CT) imaging and clinical features. Methods: We conducted a retrospective cohort study in 11 Japanese tertiary care facilities that treated COVID-19 patients. Participants were tested using both real-time reverse transcription polymerase chain reaction (RT-PCR) and chest CTs between January 1 and May 30, 2020. We chronologically split the dataset in each hospital into training and test sets, containing patients in a 7:3 ratio. A Light Gradient Boosting Machine model was used for the analysis. Results: A total of 703 patients were included, and two models-the full model and the A-blood model-were developed for their diagnosis. The A-blood model included eight variables (the Ali-M3 confidence, along with seven clinical features of blood counts and biochemistry markers). The areas under the receiver-operator curve of both models [0.91, 95% confidence interval (CI): 0.86 to 0.95 for the full model and 0.90, 95% CI: 0.86 to 0.94 for the A-blood model] were better than that of the Ali-M3 confidence (0.78, 95% CI: 0.71 to 0.83) in the test set. Conclusions: The A-blood model, a COVID-19 diagnostic model developed in this study, combines machine-learning and CT evaluation with blood test data and performs better than the Ali-M3 framework existing for this purpose. This would significantly aid physicians in making a quicker diagnosis of COVID-19.

Impact of diabetes and Krebs von den Lungen-6 on coronavirus disease 2019 severity: A single-center study from Japan.

AIMS/INTRODUCTION: Diabetes mellitus is reported as a risk factor for increased coronavirus disease 2019 (COVID-19) severity and mortality, but there have been few reports from Japan. Associations between diabetes mellitus and COVID-19 severity and mortality were investigated in a single Japanese hospital. MATERIALS AND METHODS: Patients aged ≥20 years admitted to Osaka City General Hospital for COVID-19 treatment between April 2020 and March 2021 were included in this retrospective, observational study. Multivariable logistic regression analysis was carried out to examine whether diabetes mellitus contributes to COVID-19-related death and severity. RESULTS: Of the 262 patients included, 108 (41.2%) required invasive ventilation, and 34 (13.0%) died in hospital. The diabetes group (n = 92) was significantly older, more obese, had longer hospital stays, more severe illness and higher mortality than the non-diabetes group (n = 170). On multivariable logistic regression analysis, age (odds ratio [OR] 1.054, 95% confidence interval [CI] 1.023-1.086), body mass index (OR 1.111, 95% CI 1.028-1.201), history of diabetes mellitus (OR 2.429, 95% CI 1.152-5.123), neutrophil count (OR 1.222, 95% CI 1.077-1.385), C-reactive protein (OR 1.096, 95% CI 1.030-1.166) and Krebs von den Lungen-6 (OR 1.002, 95% CI 1.000-1.003) were predictors for COVID-19 severity (R2 = 0.468). Meanwhile, age (OR 1.104, 95% CI 1.037-1.175) and Krebs von den Lungen-6 (OR 1.003, 95% CI 1.001-1.005) were predictors for COVID-19-related death (R2 = 0.475). CONCLUSIONS: Diabetes mellitus was a definite risk factor for COVID-19 severity in a single Japanese hospital treating moderately-to-severely ill patients.

Erdheim-Chester Disease Involving the Central Nervous System with Latent Toxoplasmosis.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis characterized by the infiltration of foamy histiocytes into multiple organs. We herein report a case of ECD with central nervous system (CNS) involvement in a 63-year-old man who also presented a positive result for Toxoplasma gondii nested polymerase chain reaction testing of cerebrospinal fluid. Since anti-Toxoplasma treatment proved completely ineffective, we presumed latent infection of the CNS with T. gondii. This case suggests the difficulty of distinguishing ECD with CNS involvement from toxoplasmic encephalitis and the possibility of a relationship between the pathogeneses of ECD and infection with T. gondii.