Nationwide survey in Japan of the causative diseases of bloody sputum and hemoptysis in departments of respiratory medicine at university hospitals and core hospitals.

BACKGROUND: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan. METHODS: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan. RESULTS: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%). CONCLUSIONS: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account.

Clinical features relating to pneumococcal colony phase variation in hospitalized adults with pneumonia.

Background. Streptococcus pneumoniae is a major causative bacteria of pneumonia and invasive pneumococcal disease (IPD); however, the mechanisms underlying its severity and invasion remain to be defined. Pneumococcal colonies exhibit opaque and transparent opacity phase variations, which have been associated with invasive infections and nasal colonization, respectively, in animal studies. This study evaluated the relationship between the opacity of pneumococcal colonies and the clinical presentation of pneumococcal pneumonia.Methods. This retrospective study included adult patients hospitalized with pneumococcal pneumonia between 2012 and 2019 at four tertiary medical institutions. Pneumococcal strains from lower respiratory tract specimens were determined for their serotypes and microscopic colony opacity, and the association between the opacity phase and the severity of pneumonia was evaluated. Serotypes 3 and 37 with mucoid colony phenotypes were excluded from the study because their colony morphologies were clearly different.Results. A total of 92 patients were included. Most patients were older adults (median age: 72 years) and males (67 %), and 59 % had community-acquired pneumonia. Of the 92 patients, 41 (45 %), 12 (13 %), and 39 (42 %) patients had opaque, transparent, and mixed variants in their pneumococcal colony, respectively. The opaque and non-opaque pneumococcal variants had no statistically significant difference in patient backgrounds. Although the pneumonia severity index score did not differ between the opaque and non-opaque groups, the rate of bacteremia was significantly higher in the opaque group than in the non-opaque group. Serotype distribution was similar between the groups.Conclusions. Opaque pneumococcal variants may cause pneumonia and invasive diseases in humans. This study could help elucidate IPD, and opacity assessment may serve as a predictor for IPD.

Efficacy of Intrathecal Isoniazid and Steroid Therapy in Refractory Tuberculous Meningitis.

Tuberculous meningitis is an infectious disease with high mortality. Literature describing intrathecal therapy for tuberculous meningitis is scarce. We herein report a case of refractory tuberculous meningitis in a 52-year-old woman with underlying neuropsychiatric systemic lupus erythematosus. Despite systemic treatment with anti-tuberculosis drugs and dexamethasone, her meningeal irritation deteriorated. Intrathecal isoniazid and prednisolone administration was therefore initiated, and the symptoms of severe meningeal irritation improved along with head magnetic resonance imaging and cerebrospinal fluid findings. This case report highlights the efficacy of intrathecal isoniazid and steroid injections for refractory tuberculous meningitis, particularly in patients with severe meningeal irritation.

A high α1-antitrypsin/interleukin-10 ratio predicts bacterial pneumonia in adults with community-acquired pneumonia: a prospective cohort study.

BACKGROUND: Current microbiological tests fail to identify the causative microorganism in more than half of all pneumonia cases. We explored biomarkers that could be used for differentiating between bacterial and viral pneumonia in patients with community-acquired pneumonia (CAP). METHODS: In this prospective cohort study conducted in Japan, data obtained from adult patients with bacterial pneumonia, including bacterial and viral coinfections (bacterial pneumonia [BP] group), and purely viral pneumonia (VP group) at diagnosis were analyzed using multivariate logistic regression analysis to identify predictors of bacterial pneumonia. Furthermore, a decision tree was developed using the predictors. RESULTS: A total of 210 patients were analyzed. The BP and VP groups comprised 108 and 18 patients, respectively. The other 84 patients had no identified causative microorganism. The two groups shared similar characteristics, including disease severity; however, a significant difference (p < 0.05) was observed between the two groups regarding sputum type; sputum volume score; neutrophil counts; and serum levels of interleukin (IL)-8, IL-10, and α1-antitrypsin (AAT). Sputum volume score (p < 0.001), IL-10 (p < 0.001), and AAT (p = 0.008) were ultimately identified as predictors of BP. The area under the curve for these three variables on the receiver operating characteristic (ROC) curve was 0.927 (95% confidence interval [CI]: 0.881-0.974). The ROC curve for sputum volume score and an AAT/IL-10 ratio showed a diagnostic cutoff of 1 + and 65, respectively. Logistic regression analysis using dichotomized variables at the cutoff values showed that the odds ratios for the diagnosis of BP were 10.4 (95% CI: 2.2-50.2) for sputum volume score (absence vs. presence) and 19.8 (95% CI: 4.7-83.2) for AAT/IL-10 ratio (< 65 vs. ≥ 65). CONCLUSIONS: Considering that obtaining a definitive etiologic diagnosis with the current testing methods is difficult and time consuming, a decision tree with two predictors, namely sputum volume and the AAT/IL-10 ratio, can be useful in predicting BP among patients diagnosed with CAP and facilitating the appropriate use of antibiotics. TRIAL REGISTRATION: UMIN000034673 registered on November 29, 2018.

Safety and efficacy of 5-aminolevulinic acid phosphate/iron in mild-to-moderate coronavirus disease 2019: A randomized exploratory phase II trial.

BACKGROUND: 5-aminolevulinic acid (5-ALA), a natural amino acid that is marketed alongside sodium ferrous citrate (SFC) as a functional food, blocks severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proliferation in vitro and exerts anti-inflammatory effects. In this phase II open-label, prospective, parallel-group, randomized trial, we aimed to evaluate the safety and efficacy of 5-ALA in patients with mild-to-moderate coronavirus disease 2019. METHODS: This trial was conducted in patients receiving 5-ALA/SFC (250/145 mg) orally thrice daily for 7 days, followed by 5-ALA/SFC (150/87 mg) orally thrice daily for 7 days. The primary endpoints were changes in SARS-CoV-2 viral load, clinical symptom scores, and 5-ALA/SFC safety (adverse events [AE] and changes in laboratory values and vital signs). RESULTS: A total of 50 patients were enrolled from 8 institutions in Japan. The change in SARS-CoV-2 viral load from baseline was not significantly different between the 5-ALA/SFC (n = 24) and control (n = 26) groups. The duration to improvement was shorter in the 5-ALA/SFC group than in the control group, although the difference was not significant. The 5-ALA/SFC group exhibited faster improvement rates in "taste abnormality," "cough," "lethargy," and "no appetite" than the control group. Eight AEs were observed in the 5-ALA/SFC group, with 22.7% of patients experiencing gastrointestinal symptoms (decreased appetite, constipation, and vomiting). AEs occurred with 750/435 mg/day in 25.0% of patients in the first phase and with 450/261 mg/day of 5-ALA/SFC in 6.3% of patients in the second phase. CONCLUSION: 5-ALA/SFC improved some symptoms but did not influence the SARS-CoV-2 viral load or clinical symptom scores over 14 days. The safety of 5-ALA/SFC in this study was acceptable. Further evaluation using a larger sample size or modified method is warranted.

A novel ex vivo lung cancer model based on bioengineered rat lungs.

Introduction: Two-dimensional cell cultures have contributed substantially to lung cancer research, but 3D cultures are gaining attention as a new, more efficient, and effective research model. A model reproducing the 3D characteristics and tumor microenvironment of the lungs in vivo, including the co-existence of healthy alveolar cells with lung cancer cells, is ideal. Here, we describe the creation of a successful ex vivo lung cancer model based on bioengineered lungs formed by decellularization and recellularization. Methods: Human cancer cells were directly implanted into a bioengineered rat lung, which was created with a decellularized rat lung scaffold reseeded with epithelial cells, endothelial cells and adipose-derived stem cells. Four human lung cancer cell lines (A549, PC-9, H1299, and PC-6) were applied to demonstrate forming cancer nodules on recellularized lungs and histopathological assessment were made among these models. MUC-1 expression analysis, RNA-seq analysis and drug response test were performed to demonstrate the superiority of this cancer model. Results: The morphology and MUC-1 expression of the model were like those of lung cancer in vivo. RNA sequencing revealed an elevated expression of genes related to epithelial-mesenchymal transition, hypoxia, and TNF-α signaling via NF-κB; but suppression of cell cycle-related genes including E2F. Drug response assays showed that gefitinib suppressed PC-9 cell proliferation equally well in the 3D lung cancer model as in 2D culture dishes, albeit over a smaller volume of cells, suggesting that fluctuations in gefitinib resistance genes such as JUN may affect drug sensitivity. Conclusions: A novel ex vivo lung cancer model was closely reproduced the 3D structure and microenvironment of the actual lungs, highlighting its possible use as a platform for lung cancer research and pathophysiological studies.

Decreased community-acquired pneumonia coincided with rising awareness of precautions before governmental containment policy in Japan.

The effectiveness of population-wide compliance to personal precautions (mask-wearing and hand hygiene) in preventing community-acquired pneumonia has been unknown. In Japan, different types of nonpharmaceutical interventions from personal precautions to containment and closure policies (CACPs, e.g. stay-at-home requests) were sequentially introduced from late January to April 2020, allowing for separate analysis of the effects of personal precautions from other more stringent interventions. We quantified the reduction in community-acquired pneumonia hospitalizations and deaths and assessed if it coincided with the timing of increased public awareness of personal precautions before CACPs were implemented. A quasi-experimental interrupted time-series design was applied to non-COVID-19 pneumonia hospitalization and 30-day death data from April 2015 to August 2020 across Japan to identify any trend changes between February and April 2020. We also performed a comparative analysis of pyelonephritis and biliary tract infections to account for possible changes in the baseline medical attendance. These trend changes were then compared with multiple indicators of public awareness and behaviors related to personal precautions, including keyword usage in mass media coverage and sales of masks and hand hygiene products. Hospitalizations and 30-day deaths from non-COVID-19 pneumonia dropped by 24.3% (95% CI 14.8-32.8) and 16.1% (5.5-25.5), respectively, in February 2020, before the implementation of CACPs, whereas pyelonephritis and biliary tract infections did not suggest a detectable change. These changes coincided with increases in indicators related to personal precautions rather than those related to contact behavior changes. Community-acquired pneumonia could be reduced by population-wide compliance to moderate precautionary measures.

Effect of voluntary human mobility restrictions on vector-borne diseases during the COVID-19 pandemic in Japan: A descriptive epidemiological study using a national database (2016 to 2021).

The coronavirus disease 2019 (COVID-19) pandemic not only encouraged people to practice good hygiene but also caused behavioral inhibitions and resulted reduction in both endemic and imported infectious diseases. However, the changing patterns of vector-borne diseases under human mobility restrictions remain unclear. Hence, we aimed to investigate the impact of transborder and local mobility restrictions on vector-borne diseases through a descriptive epidemiological study. The analysis was conducted using data from the National Epidemiological Surveillance of Infectious Diseases system in Japan. We defined the pre-pandemic period as the period between the 1st week of 2016 to the 52nd week of 2019 and defined the pandemic period as from the 1st week of 2020 to the 52nd week of 2021, with the assumption that human mobility was limited throughout the pandemic period. This study addressed 24 diseases among notifiable vector borne diseases. Datasets were obtained from weekly reports from the National Epidemiological Surveillance of Infectious Diseases, and the incidence of each vector-borne disease was examined. Interrupted time series analysis was conducted on the epidemic curves for the two periods. Between the pre- and post-pandemic periods, the incidence of dengue fever and malaria significantly decreased, which may be related to limited human transboundary mobility (p = 0.003/0.002). The incidence of severe fever with thrombocytopenia syndrome, scrub typhus, and Japanese spotted fever did not show changes between the two periods or no association with human mobility. This study suggests that behavioral control may reduce the incidence of new mosquito-borne diseases from endemic areas but may not affect tick-borne disease epidemics within an endemic area.

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets.

Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs. Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation. Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases. Conclusions: The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the GTF2I mutation. These findings suggest that the existence of the GTF2I mutation might be related to indolent types of TETs, and RAS mutations could be candidates as therapeutic targets in TETs.

Echinocandin Resistance in Candida auris Occurs in the Murine Gastrointestinal Tract Due to FKS1 Mutations.

Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro.

Impact of G29179T mutation on two commercial PCR assays for SARS-CoV-2 detection.

Nucleic acid amplification test (NAAT) is the gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. However, genetic mutations in the virus can affect the result. Cycle threshold (Ct) values of N genes and their association with mutations using SARS-CoV-2 positive specimens diagnosed by the Xpert Xpress SARS-CoV-2 were examined in this study. In total, 196 nasopharyngeal swab specimens were tested for SARS-CoV-2 infection using the Xpert Xpress SARS-CoV-2, and 34 were positive. WGS was performed for four outlier samples with increased ΔCt identified by Scatterplot analysis as well as seven control samples without increased ΔCt in the Xpert Xpress SARS-CoV-2. The presence of the G29179T mutation was identified as a cause of increased ΔCt. PCR using the Allplex™ SARS-CoV-2 Assay did not show a similar increase in ΔCt. Previous reports focusing on N-gene mutations and their effects on SARS-CoV-2 testing including the Xpert Xpress SARS-CoV-2 were also summarized. While a single mutation that impacts one target of a multiplex NAAT is not a true detection failure, mutation compromising NAAT target region can cause confusion of the results and render the assay susceptible to diagnostic failure.

Pulmonary Langerhans Cell Histiocytosis That Progressed from a Single-system to a Multisystem Form despite Smoking Cessation.

A 36-year-old Japanese man presented with cavities and nodular shadows in the lower lobes of his lungs and osteolytic lesions in the thoracic spine. He was diagnosed with multisystem Langerhans cell histiocytosis (LCH). Three years earlier, he had been noted to have small cavities and granular lesions noted in the upper lobes of his lungs, which later improved with smoking cessation. It was likely that his single-system pulmonary LCH (PLCH) progressed to multisystem LCH despite smoking cessation. Relapse or progression may occur in cases where PLCH lesions improve after smoking cessation. Thus, close follow-up is vital.

Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome.

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

Evaluation of a Triage Checklist for Mild COVID-19 Outpatients in Predicting Subsequent Emergency Department Visits and Hospitalization during the Isolation Period: A Single-Center Retrospective Study.

Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age > 50 years, body mass index > 25 kg/m2, hypertension, tachycardia with pulse rate > 100/min or blood pressure > 135 mmHg at triage, and >3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization.

Efficacy of Lactococcus lactis strain plasma (LC-Plasma) in easing symptoms in patients with mild COVID-19: protocol for an exploratory, multicentre, double-blinded, randomised controlled trial (PLATEAU study).

INTRODUCTION: The COVID-19 pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remain limited. Since the oral intake of Lactococcus lactis strain plasma (LC-Plasma) enhances both the innate and acquired immune systems through the activation of plasmacytoid dendritic cells (pDCs), we hypothesised that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19. METHODS AND ANALYSIS: This is an exploratory, multicentre, double-blinded, randomised, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 subjects×2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors and the proportion of subjects with emergency room visits to medical institutions or who are hospitalised. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported in journal publications. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (registration number: jRCTs071210097).

Characteristics and Clinical Ocular Manifestations in Patients with Acute Corneal Graft Rejection after Receiving the COVID-19 Vaccine: A Systematic Review.

This study aimed to determine the characteristics and clinical ocular manifestations of acute corneal graft rejection after coronavirus disease 2019 (COVID-19) vaccination. We conducted an online search of the PubMed and EMBASE databases. Data on recipients' characteristics, corneal transplantation types, interval between vaccination and allograft rejection, clinical manifestations, and graft rejection medication were extracted. Thirteen articles on 21 patients (23 eyes) with acute corneal graft rejection after COVID-19 vaccination, published between April and December 2021, were included. The median (interquartile range) age at the onset of rejection was 68 (27-83) years. Types of transplantation included penetrating keratoplasty (12 eyes), Descemet membrane endothelial keratoplasty (six eyes), Descemet stripping automated endothelial keratoplasty (four eyes), and living-related conjunctival-limbal allograft (one eye). The interval between vaccination and rejection ranged from 1 day to 6 weeks. Corneal edema was the leading clinical manifestation (20 eyes), followed by keratic precipitates (14 eyes) and conjunctival or ciliary injection (14 eyes). Medications included frequently applied topical corticosteroids (12 eyes), followed by a combination of topical and oral corticosteroids (four eyes). In addition, the clinical characteristics of corneal allograft rejection after COVID-19 vaccination were identified. Corneal transplant recipients may require further vaccination, necessitating appropriate management and treatment.

Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from Japanese Spotted Fever.

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF.

Comparison of liposomal amphotericin B alone and in combination with flucytosine in the treatment of non-HIV Cryptococcal meningitis: A nationwide observational study.

BACKGROUND: Cryptococcal meningitis (CM) is an opportunistic infectious disease that occurs in immunocompromised hosts, not only in patients living with HIV, but also in patients without HIV. The evidence regarding the treatment for CM in patients without HIV is mainly found in small retrospective studies and is extremely limited. OBJECTIVES: In the present study, we compared the efficacy of liposomal amphotericin B (L-AMB) alone and in combination with flucytosine (5-FC) for the induction treatment of CM in patients without HIV. PATIENTS/METHODS: Data were gathered from the Japanese Diagnosis Procedure Combination database obtained from hospitals throughout Japan. The study included 517 patients without HIV but having CM who fulfilled the inclusion and exclusion criteria. We analysed the average effect of adding 5-FC to L-AMB treatment using the survival time within 14 days of the diagnosis after adjustment of the baseline clinical characteristics with associations with both selections of the treatment and the prognosis. RESULTS: A total of 146 and 217 CM patients received L-AMB and L-AMB with 5-FC, respectively, within 7 days of diagnosis. L-AMB with 5-FC showed better prognosis than L-AMB on day 14 (mortality 6% vs. 11%, hazard ratio, 0.5775; 95% confidence interval, 0.2748-1.213; p = 0.1, Wald test). CONCLUSIONS: From the results of this real-world database study, we revealed that the combination therapy of 5-FC on L-AMB for induction therapy might have an advantage on the survival time of NHNT patients with CM as well as PLHIV patients with CM.