研究者詳細 - 南宮　湖

論文 - 南宮　湖

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Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials.

Fujiwara Y, Horita N, Harrington M, Namkoong H, Miyashita H, Galsky MD

Cancer immunology, immunotherapy : CII 71 （ 12 ） 2837 - 2848 2022年12月

ISSN 0340-7004

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Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study

K Nakagawara, S Chubachi, H Namkoong, H Tanaka, H Lee, S Azekawa, ...

Respiratory Research 23 (1), 315 23 （ 1 ） 315 - 315 2022年11月

ISSN 1465-9921

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

G Butler-Laporte, G Povysil, JA Kosmicki, ET Cirulli, T Drivas, S Furini, ...

PLoS genetics 18 (11), e1010367 （Public Library of Science (PLoS)） 18 （ 11 ） e1010367 - e1010367 2022年11月

ISSN 1553-7404

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10<sup>-7</sup>). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

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Prophylactic antibiotics for postcataract surgery endophthalmitis: a systematic review and network meta-analysis of 6.8 million eyes

A Kato, N Horita, H Namkoong, E Nomura, N Masuhara, T Kaneko, ...

Scientific Reports 12 (1), 17416 12 （ 1 ） 17416 - 17416 2022年10月

ISSN 2045-2322

To reveal optimal antibiotic prophylactic regimen for postoperative endophthalmitis (POE), we conducted systematic review and network meta-analysis. A total of 51 eligible original articles, including two randomized controlled trials, were identified. In total, 4502 POE cases occurred in 6,809,732 eyes (0.066%). Intracameral injection of vancomycin had the best preventive effect (odds ratio [OR] 0.03, 99.6% confidence interval [CI] 0.00-0.53, corrected P-value = 0.006, P-score = 0.945) followed by intracameral injection of cefazoline (OR 0.09, 99.6% CI 0.02-0.42, corrected P-value < 0.001, P-score = 0.821), cefuroxime (OR 0.18, 99.6% CI 0.09-0.35, corrected P-value < 0.001, P-score = 0.660), and moxifloxacin (OR 0.36, 99.6% CI 0.16-0.79, corrected P-value = 0.003, P-score = 0.455). While one randomized controlled trial supported each of intracameral cefuroxime and moxifloxacin, no randomized controlled trial evaluated vancomycin and cefazoline. Sensitivity analysis focusing on the administration route revealed that only intracameral injection (OR 0.19, 99.4% CI 0.12-0.30, corrected P-value < 0.001, P-score = 0.726) significantly decreased the risk of postoperative endophthalmitis. In conclusion, intracameral injection of either vancomycin, cefazoline, cefuroxime, or moxifloxacin prevented POE.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant

S Mise-Omata, M Ikeda, M Takeshita, Y Uwamino, M Wakui, T Arai, ...

The Journal of Immunology 209 (11), 2104-2113 209 （ 11 ） 2104 - 2113 2022年10月

ISSN 0022-1767

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

H Salvator, A Cheng, LB Rosen, PR Williamson, JE Bennett, A Kashyap, ...

Respiratory Research 23 (1), 1-9 23 （ 1 ） 280 - 280 2022年10月

ISSN 1465-9921

BACKGROUND: Anti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear. Therefore, we examined anti-GM-CSF autoantibodies to determine whether amount or neutralizing activity could distinguish between groups. METHODS: Plasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n = 15), cryptococcal meningitis (n = 15), severe nocardiosis (n = 5) or overlapping phenotypes (n = 6) were compared. The relative amount of aAb was assessed using a particle-based approach, reported as a mouse monoclonal anti-human GM-CSF as standard curve and expressed in an arbitrary Mouse Monoclonal Antibody Unit (MMAU). The neutralizing activity of the plasma was assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes. RESULTS: Anti-GM-CSF aAb relative amounts were higher in PAP patients compared to those with cryptococcosis (mean 495 ± 464 MMAU vs 197 ± 159 MMAU, p = 0.02); there was no difference with patients with nocardiosis (430 ± 493 MMAU) nor between the two types of infections. The dilution of plasma resulting in 50% inhibition of GM-CSF-induced pSTAT5 (approximate IC50) did not vary appreciably across groups of patients (1.6 ± 3.1%, 3.9 ± 6% and 1.8 ± 2.2% in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in the presence of 10 MMAU of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti-GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels. CONCLUSIONS: Despite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

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Clinical clustering with prognostic implications in Japanese COVID-19 patients: report from Japan COVID-19 Task Force, a nation-wide consortium to investigate COVID-19 host genetics

Otake Shiro, Chubachi Shotaro, Namkoong Ho, Nakagawara Kensuke, Tanaka Hiromu, Lee Ho, Morita Atsuho, Fukushima Takahiro, Watase Mayuko, Kusumoto Tatsuya, Masaki Katsunori, Kamata Hirofumi, Ishii Makoto, Hasegawa Naoki, Harada Norihiro, Ueda Tetsuya, Ueda Soichiro, Ishiguro Takashi, Arimura Ken, Saito Fukuki, Yoshiyama Takashi, Nakano Yasushi, Mutoh Yoshikazu, Suzuki Yusuke, Murakami Koji, Okada Yukinori, Koike Ryuji, Kitagawa Yuko, Kimura Akinori, Imoto Seiya, Miyano Satoru, Ogawa Seishi, Kanai Takanori, Fukunaga Koichi

BMC INFECTIOUS DISEASES 22 （ 1 ） 735 - 735 2022年09月

BACKGROUND: The clinical course of coronavirus disease (COVID-19) is diverse, and the usefulness of phenotyping in predicting the severity or prognosis of the disease has been demonstrated overseas. This study aimed to investigate clinically meaningful phenotypes in Japanese COVID-19 patients using cluster analysis. METHODS: From April 2020 to May 2021, data from inpatients aged ≥ 18 years diagnosed with COVID-19 and who agreed to participate in the study were collected. A total of 1322 Japanese patients were included. Hierarchical cluster analysis was performed using variables reported to be associated with COVID-19 severity or prognosis, namely, age, sex, obesity, smoking history, hypertension, diabetes mellitus, malignancy, chronic obstructive pulmonary disease, hyperuricemia, cardiovascular disease, chronic liver disease, and chronic kidney disease. RESULTS: Participants were divided into four clusters: Cluster 1, young healthy (n = 266, 20.1%); Cluster 2, middle-aged (n = 245, 18.5%); Cluster 3, middle-aged obese (n = 435, 32.9%); and Cluster 4, elderly (n = 376, 28.4%). In Clusters 3 and 4, sore throat, dysosmia, and dysgeusia tended to be less frequent, while shortness of breath was more frequent. Serum lactate dehydrogenase, ferritin, KL-6, D-dimer, and C-reactive protein levels tended to be higher in Clusters 3 and 4. Although Cluster 3 had a similar age as Cluster 2, it tended to have poorer outcomes. Both Clusters 3 and 4 tended to exhibit higher rates of oxygen supplementation, intensive care unit admission, and mechanical ventilation, but the mortality rate tended to be lower in Cluster 3. CONCLUSIONS: We have successfully performed the first phenotyping of COVID-19 patients in Japan, which is clinically useful in predicting important outcomes, despite the simplicity of the cluster analysis method that does not use complex variables.

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Immune Checkpoint Inhibitors Do Not Increase Short-Term Risk of Hypertension in Cancer Patients: a Systematic Literature Review and Meta-Analysis

S Minegishi, S Kinguchi, N Horita, H Namkoong, A Briasoulis, T Ishigami, ...

Hypertension 79 (11), 2611-2621 79 （ 11 ） 101161HYPERTENSIONAHA12219865 - 2621 2022年09月

ISSN 0194-911X

BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

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Immune checkpoint inhibitor-induced arthralgia is tightly associated with improved overall survival in cancer patients

Maeda Ayaka, Takase-Minegishi Kaoru, Kirino Yohei, Hamada Naoki, Kunishita Yosuke, Yoshimi Ryusuke, Meguro Akira, Namkoong Ho, Horita Nobuyuki, Nakajima Hideaki

RHEUMATOLOGY 62 （ 4 ） 1451 - 1459 2022年09月

ISSN 1462-0324

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs), arthralgia has been the most commonly reported musculoskeletal immune-related adverse events (irAEs). We aimed to characterise arthralgia and its association with overall survival (OS). METHODS: Randomised controlled trials (RCTs) reporting data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for arthralgia using a random effects model meta-analysis. Individual patient data were reconstructed from RCTs, assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14,377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20-1.56). Of the 369 patients in YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs; noticeably more frequently vs. those without arthralgia (OR 1.92, 95% CI 1.04-3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80-8.39). In the YCU registry, patients with (vs. without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17-0.65, P < 0.001). CONCLUSION: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS and patients' condition must be carefully evaluated to determine optimal management.

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Clinical significance of prediabetes, undiagnosed diabetes and diagnosed diabetes on critical outcomes in COVID-19: Integrative analysis from the Japan COVID-19 task force

Fukushima Takahiro, Chubachi Shotaro, Namkoong Ho, Asakura Takanori, Tanaka Hiromu, Lee Ho, Azekawa Shuhei, Okada Yukinori, Koike Ryuji, Kimura Akinori, Imoto Seiya, Miyano Satoru, Ogawa Seishi, Kanai Takanori, Fukunaga Koichi

DIABETES OBESITY & METABOLISM 25 （ 1 ） 144 - 155 2022年09月

ISSN 1462-8902

AIM: Diabetes mellitus (DM) is a known risk factor for severe coronavirus disease 2019 (COVID-19), but the clinical impact of undiagnosed diabetes and prediabetes in COVID-19 are unclear particularly in Japan. We clarify the difference in clinical characteristics, including age, sex, body mass index and co-morbidities, laboratory findings and critical outcomes, in a large Japanese COVID-19 cohort without diabetes, with prediabetes, undiagnosed diabetes and diagnosed diabetes, and to identify associated risk factors. MATERIALS AND METHODS: This multicentre, retrospective cohort study used the Japan COVID-19 Task Force database, which included data on 2430 hospitalized COVID-19 patients from over 70 hospitals from February 2020 to October 2021. The prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes were estimated based on HbA1c levels or a clinical diabetes history. Critical outcomes were defined as the use of high-flow oxygen, invasive positive-pressure ventilation or extracorporeal membrane oxygenation, or death during hospitalization. RESULTS: Prediabetes, undiagnosed diabetes and diagnosed diabetes were observed in 40.9%, 10.0% and 23.0%, respectively. Similar to diagnosed diabetes, prediabetes and undiagnosed diabetes were risk factors for critical COVID-19 outcomes (adjusted odds ratio [aOR] [95% CI]: 2.13 [1.31-3.48] and 4.00 [2.19-7.28], respectively). HbA1c was associated with COVID-19 severity in prediabetes patients (aOR [95% CI]: 11.2 [3.49-36.3]), but not other groups. CONCLUSIONS: We documented the clinical characteristics and outcomes of Japanese COVID-19 patients according to HbA1c levels or diabetes co-morbidity. As well as undiagnosed and diagnosed diabetes, physicians should be aware of prediabetes related to COVID-19 severity.

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Identification of trypsin-degrading commensals in the large intestine

Y Li, E Watanabe, Y Kawashima, DR Plichta, Z Wang, M Ujike, QY Ang, ...

Nature 609 (7927), 582-589 609 （ 7927 ） 582 - 589 2022年09月

ISSN 0028-0836

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1-3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.

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Effects of mild obesity on outcomes in Japanese patients with COVID-19: a nationwide consortium to investigate COVID-19 host genetics

H Lee, S Chubachi, H Namkoong, H Tanaka, S Otake, K Nakagawara, ...

Nutrition & Diabetes 12 (1), 38 12 （ 1 ） 38 - 38 2022年08月

ISSN 2044-4052

BACKGROUND: Obesity is reported to be a risk factor for severe disease in patients with coronavirus disease 2019 (COVID-19). However, there are no specific reports on the risk of severe disease according to body mass index (BMI) in Japan. Thus, this study aimed to investigate the effect of obesity stratified by BMI on the severity of COVID-19 in the general Japanese population. METHODS: From February 2020 to May 2021, 1 837 patients aged ≥18 years were enrolled in the Japan COVID-19 Task Force. Patients with known BMI and disease severity were analyzed. Severity was defined as critical if the patient was treated in the intensive care unit, required invasive mechanical ventilation, or died. RESULTS: Class 1 obesity (25.0 ≤ BMI < 30.0 kg/m2), class 2 obesity (30.0 ≤ BMI < 35.0 kg/m2), and class 3 or 4 obesity (BMI ≥ 35 kg/m2) were present in 29%, 8%, and 3% of the cases, respectively. Multiple logistic regression analysis with known risk factors for critical illness indicated that class 2 obesity was an independent risk factor for oxygenation (adjusted odds ratio, 4.75) and critical cases (adjusted odds ratio, 1.81). Class 1 obesity and class 3 or 4 obesity were independent risk factors for oxygen administration (adjusted odds ratios 2.01 and 3.12, respectively), but not for critical cases. However, no differences in the mortality rates were observed between the BMI classes (P = 0.5104). CONCLUSION: Obesity is a risk factor for respiratory failure in Japanese patients with COVID-19, regardless of the degree of obesity. However, it may not cause severe COVID-19 in a dose-response relationship with BMI. COVID-19 patients with mild obesity may benefit from aggressive intensive care.

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Dynamics of antibody titers and cellular immunity among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine

Y Uwamino, T Kurafuji, K Takato, A Sakai, A Tanabe, M Noguchi, ...

Vaccine 40 (32), 4538-4543 40 （ 32 ） 4538 - 4543 2022年07月

ISSN 0264-410X

BACKGROUND: The antibody titer is known to wane within months after receiving two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine. However, knowledge of the cellular immune response dynamics following vaccination is limited. This study to aimed to determine antibody and cellular immune responses following vaccination, and the incidence and determinants of breakthrough infection. METHODS: This prospective cohort study a 6-month follow-up period was conducted among Japanese healthcare workers. All participants received two doses of BNT162b2 vaccine. Anti-SARS-CoV-2 antibody titers and T-cell immune responses were measured in serum samples collected at several timepoints before and after vaccination. RESULTS: A total of 608 participants were included in the analysis. Antibody titers were elevated 3 weeks after vaccination and waned over the remainder of the study period. T-cell immune responses showed similar dynamics. Six participants without predisposing medical conditions seroconverted from negative to positive on the IgG assay for nucleocapsid proteins, indicating breakthrough SARS-CoV-2 infection. Five of the six breakthrough infections were asymptomatic. CONCLUSIONS: Both humoral and cellular immunity waned within 6 months after BNT162b2 vaccination. The incidence of asymptomatic breakthrough infection within 6 months after vaccination was approximately one percent. UMIN CLINICAL TRIALS REGISTRY ID: UMIN000043340.

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U-shaped association between abnormal serum uric acid levels and COVID-19 severity: reports from the Japan COVID-19 Task Force

T Fukushima, S Chubachi, H Namkoong, S Otake, K Nakagawara, ...

International Journal of Infectious Diseases 122, 747-754 122 747 - 754 2022年07月

ISSN 1201-9712

OBJECTIVES: This study aimed to identify the relationship between abnormal serum uric acid levels or a history of hyperuricemia and coronavirus disease 2019 (COVID-19) severity in the Japanese population. METHODS: We included 1,523 patients enrolled in the Japan COVID-19 Task Force cohort between February 2020 and May 2021. We compared the clinical characteristics, including comorbidities, laboratory findings, and outcomes, particularly invasive mechanical ventilation (IMV), among patients with and without abnormal uric acid levels or a history of hyperuricemia. RESULTS: Patients with high serum uric acid levels were older and had higher body weights and body mass index than those without. In addition, the multiple logistic regression analysis revealed a significant association between high serum uric acid levels or a history of hyperuricemia and an increased risk of IMV (odds ratio (OR)=1.77; p=0.03/OR=1.56; p=0.04). Moreover, patients with low uric acid levels on admission were also associated significantly with the requirement of IMV (OR=5.09; p<0.0001). CONCLUSION: Abnormal serum uric acid levels or a history of hyperuricemia were significantly associated with COVID-19 severity in the Japanese cohort.

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system

Ozawa Takuya, Namkoong Ho, Takaya Risako, Takahashi Yusuke, Fukunaga Koichi, Enoki Yuki, Taguchi Kazuaki, Kizu Junko, Matsumoto Kazuaki, Hasegawa Naoki

BMC INFECTIOUS DISEASES 22 （ 1 ） 2022年06月

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

Ozawa T, Namkoong H, Takaya R, Takahashi Y, Fukunaga K, Enoki Y, Taguchi K, Kizu J, Matsumoto K, Hasegawa N

BMC infectious diseases 22 （ 1 ） 580 2022年06月

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

Takuya Ozawa, Ho Namkoong, Risako Takaya, Yusuke Takahashi, Koichi Fukunaga, Yuki Enoki, Kazuaki Taguchi, Junko Kizu, Kazuaki Matsumoto, Naoki Hasegawa

BMC infectious diseases 22 （ 1 ） 580 - 580 2022年06月

BACKGROUND: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. METHODS: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. RESULTS: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The β value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type. CONCLUSIONS: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

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COMPARISON OF SARS-COV-2 VACCINE RESPONSE IN PATIENTS WITH INFLAMMATORY RHEUMATIC DISEASE; MRNA-1273 VACCINE INDUCES HIGHER HUMORAL IMMUNOGENICITY THAN BNT162B2

Kondo Y., Takeshita M., Uwamino Y., Namkoong H., Saito S., Kikuchi J., Hanaoka H., Suzuki K., Hasegawa N., Murata M., Kaneko Y.

ANNALS OF THE RHEUMATIC DISEASES 81 370 - 370 2022年06月

ISSN 0003-4967

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広域抗菌薬に対するタイムアウト「KAERUプロジェクト」の効果

瀬山翔史, 池谷修, 内田翔, 宇野俊介, 南宮湖, 上蓑義典, 尾原秀明, 荒美幸, 高野八百子, 長谷川直樹

日本環境感染学会総会プログラム・抄録集（(一社)日本環境感染学会） 37回 O50 - 1 2022年06月

Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study

H Tanaka, T Asakura, S Suzuki, S Okamori, T Kusumoto, T Ogawa, S Uno, ...

BMC Pulmonary Medicine 22 (1), 1-11 22 （ 1 ） 202 - 202 2022年05月

ISSN 1471-2466

BACKGROUND: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. METHODS: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017-September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. RESULTS: Osteoporosis (T-score ≤ - 2.5) and osteopenia (T-score - 1 to - 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50-59-, 60-69-, and 70-79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07-1.18), female sex (aOR = 36.3; 95% CI = 7.57-174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14-1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07-41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. CONCLUSIONS: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

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