研究者詳細 - 福永　興壱

論文 - 福永　興壱

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

Nakagawara K., Chubachi S., Namkoong H., Tanaka H., Lee H., Azekawa S., Otake S., Fukushima T., Morita A., Watase M., Sakurai K., Kusumoto T., Asakura T., Masaki K., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Edahiro R., Murakami K., Sato Y., Okada Y., Koike R., Kitagawa Y., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Respiratory Research 23 （ 1 ） 2022年12月

ISSN 14659921

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

Lee H., Chubachi S., Namkoong H., Tanaka H., Otake S., Nakagawara K., Morita A., Fukushima T., Watase M., Kusumoto T., Masaki K., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Murakami K., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Nutrition and Diabetes 12 （ 1 ） 2022年12月

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

Butler-Laporte G., Povysil G., Kosmicki J.A., Cirulli E.T., Drivas T., Furini S., Saad C., Schmidt A., Olszewski P., Korotko U., Quinodoz M., Çelik E., Kundu K., Walter K., Jung J., Stockwell A.D., Sloofman L.G., Jordan D.M., Thompson R.C., Del Valle D., Simons N., Cheng E., Sebra R., Schadt E.E., Kim-Schulze S., Gnjatic S., Merad M., Buxbaum J.D., Beckmann N.D., Charney A.W., Przychodzen B., Chang T., Pottinger T.D., Shang N., Brand F., Fava F., Mari F., Chwialkowska K., Niemira M., Pula S., Kenneth Baillie J., Stuckey A., Salas A., Bello X., Pardo-Seco J., Gómez-Carballa A., Rivero-Calle I., Martinón-Torres F., Ganna A., Karczewski K.J., Veerapen K., Bourgey M., Bourque G., Eveleigh R.J.M., Forgetta V., Morrison D., Langlais D., Lathrop M., Mooser V., Nakanishi T., Frithiof R., Hultström M., Lipcsey M., Marincevic-Zuniga Y., Nordlund J., Schiabor Barrett K.M., Lee W., Bolze A., White S., Riffle S., Tanudjaja F., Sandoval E., Neveux I., Dabe S., Casadei N., Motameny S., Alaamery M., Massadeh S., Aljawini N., Almutairi M.S., Arabi Y.M., Alqahtani S.A., Al Harthi F.S., Almutairi A., Alqubaishi F., Alotaibi S., Binowayn A., Alsolm E.A., Bardisy H.E., Fawzy M., Cai F., Soranzo N., Butterworth A., Center R.G., Geschwind D.H., Arteaga S., Stephens A., Butte M.J., Boutros P.C., Yamaguchi T.N.

PLoS Genetics 18 （ 11 ） 2022年11月

ISSN 15537390

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 = 5.41x10-7). 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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Upregulation of IL-4 receptor signaling pathway in circulating ILC2s from asthma patients

Baba R., Kabata H., Shirasaki Y., Kamatani T., Yamagishi M., Irie M., Watanabe R., Matsusaka M., Masaki K., Miyata J., Moro K., Uemura S., Fukunaga K.

Journal of Allergy and Clinical Immunology: Global 1 （ 4 ） 299 - 304 2022年11月

Background: Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines by stimulation with epithelial cell–derived cytokines and are implicated in the pathogenesis of various allergic diseases, including asthma. However, differences in the molecular characteristics of ILC2s between patients with asthma and healthy subjects remain unclear. Objective: We sought to evaluate differences in cytokine production capacity and gene expression profile of ILC2s in the peripheral blood of patients with asthma and healthy subjects. Methods: We evaluated ILC2s derived from 15 patients with asthma and 7 healthy subjects using flow cytometry, live-cell imaging of secretion activity analysis, and RNA-sequencing. Results: ILC2s were sorted as CD45+Lineage−CRTH2+CD127+CD161+ cells from the peripheral blood of patients with asthma and healthy subjects, and the number of ILC2s was decreased in patients with asthma (851 ± 1134 vs 2679 ± 3009 cells/20 mL blood; P = .0066). However, patient-derived ILC2s were activated to produce more IL-5 and IL-13 in response to stimulation with IL-2, IL-33, and thymic stromal lymphopoietin compared with healthy subject–derived ILC2s (P = .0032 and P = .0085, respectively). Furthermore, RNA-sequencing analysis revealed that patient-derived ILC2s had different gene expression profiles, such as increased expression in cell growth–related genes (CDKN1b, CCNG2, CCND2, CCN1), prostaglandin E receptor (PTGER2), and IL-4 receptor. In addition, a gene set of the IL-4 receptor signaling pathway was significantly upregulated in ILC2s in patients with asthma (P = .042). Conclusions: Our results suggest that circulating ILC2s in patients with asthma are preactivated via the IL-4 receptor signaling pathway and produce IL-5 and IL-13 vigorously by stimulation.

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DOCK2 is involved in the host genetics and biology of severe COVID-19

Namkoong H., Edahiro R., Takano T., Nishihara H., Shirai Y., Sonehara K., Tanaka H., Azekawa S., Mikami Y., Lee H., Hasegawa T., Okudela K., Okuzaki D., Motooka D., Kanai M., Naito T., Yamamoto K., Wang Q.S., Saiki R., Ishihara R., Matsubara Y., Hamamoto J., Hayashi H., Yoshimura Y., Tachikawa N., Yanagita E., Hyugaji T., Shimizu E., Katayama K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Aoki R., Nakamura A., Harada S., Sasano H., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K.

Nature 609 （ 7928 ） 754 - 760 2022年09月

ISSN 00280836

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

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Identification of trypsin-degrading commensals in the large intestine

Li Y., Watanabe E., Kawashima Y., Plichta D.R., Wang Z., Ujike M., Ang Q.Y., Wu R., Furuichi M., Takeshita K., Yoshida K., Nishiyama K., Kearney S.M., Suda W., Hattori M., Sasajima S., Matsunaga T., Zhang X., Watanabe K., Fujishiro J., Norman J.M., Olle B., Matsuyama S., Namkoong H., Uwamino Y., Ishii M., Fukunaga K., Hasegawa N., Ohara O., Xavier R.J., Atarashi K., Honda K.

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

ISSN 00280836

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

Fukushima T., Chubachi S., Namkoong H., Otake S., Nakagawara K., Tanaka H., Lee H., Morita A., Watase M., Kusumoto T., Masaki K., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Murakami K., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

International Journal of Infectious Diseases 122 747 - 754 2022年09月

ISSN 12019712

Objectives: This study aimed to identify the relationship between abnormal serum uric acid levels or a history of hyperuricemia and COVID-19 severity in the Japanese population. Methods: We included 1523 patients enrolled in the Japan COVID-19 Task Force cohort between February 2020 and May 2021. We compared the clinical characteristics, including co-morbidities, 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 weight 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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Real-world clinical practice for advanced non-small-cell lung cancer in the very elderly: A retrospective multicenter analysis

Fukushima T., Oyamada Y., Ikemura S., Nukaga S., Inoue T., Arai D., Ohgino K., Kuroda A., Ishioka K., Sakamaki F., Suzuki Y., Terai H., Yasuda H., Kawada I., Fukunaga K., Soejima K.

Clinical Lung Cancer 23 （ 6 ） 532 - 541 2022年09月

ISSN 15257304

Background: The optimal treatment for advanced non-small cell lung cancer (NSCLC) in very elderly patients is unclear. We aimed to evaluate their treatment in real-world clinical practice and identify suitable therapy that can improve their prognosis. Materials and methods: The medical records of 132 Japanese patients aged 80 years and older with advanced NSCLCs who were enrolled at a university hospital and its 9 affiliates were retrospectively analyzed. Clinical characteristics and overall survival (OS) were compared based on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and biomarker statuses. Patients were defined as biomarker-positive if programmed death-ligand 1 tumor proportion score (PD-L1 TPS) was ≥ 50% or activating mutations were present in epidermal growth factor receptor, anaplastic lymphoma kinase, or c-ros oncogene 1. Finally, the factors contributing to better prognosis were explored in both PS 0 - 2 and PS 3 - 4 patient groups. Results: The PS 0 - 2 patients showed a longer median OS than the PS 3 - 4 patients (5.5 vs. 1.6 months). PS 0 - 2 patients with positive biomarkers who received chemotherapy showed a significantly longer median OS than those without (18.1 vs. 3.7 months). Among the biomarker-negative/unknown PS 0 - 2 patients, the median OS showed no significant difference between those who received chemotherapy and those who did not (4.5 vs. 3.1 months). The multivariate analysis showed that treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors was related to better prognoses in the PS 0 - 2 group. Conclusion: Biomarker-matched therapy is effective even in very elderly patients. Meanwhile, the effectiveness of chemotherapy for biomarker-negative/unknown PS 0 - 2 patients is questionable.

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An Inhalation Device With Inertial Measurement Unit for Monitoring Inhaler Technique

Takano S., Shimono T., Masaki K., Fukunaga K., Kabata H., Nishie M., Ezaki T., Nakada H., Hakamata J., Hasegawa A.

IEEE/ASME Transactions on Mechatronics 27 （ 4 ） 2204 - 2211 2022年08月

ISSN 10834435

Inhalers are commonly used to treat asthma and chronic obstructive pulmonary disease. Regular and correct usage of inhalers is necessary for effective use. However, approximately 70% of patients do not use their inhalers as directed. This is due to a lack of understanding about the medication and misunderstanding of directions. Assessment of patients' inhaler techniques are usually conducted in person. However, doctors or pharmacists have no objective information regarding how patients use their inhalers at home. Therefore, monitoring daily inhaler use is necessary for precise medical treatment. This article proposes an inhalation monitoring device using an inertial measurement unit (IMU). The IMU is used to measure a patient's inhalation motion. Incorrect inhalation usage can be determined by comparing the measurement data against data that indicate correct usage. The experimental results show the utility of the proposed device.

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Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary Emphysema via Apoptosis of Alveolar Epithelial Cells

Tanosaki T., Mikami Y., Shindou H., Suzuki T., Hashidate-Yoshida T., Hosoki K., Kagawa S., Miyata J., Kabata H., Masaki K., Hamamoto R., Kage H., Miyashita N., Makita K., Matsuzaki H., Suzuki Y., Mitani A., Nagase T., Shimizu T., Fukunaga K.

Inflammation 45 （ 4 ） 1765 - 1779 2022年08月

ISSN 03603997

Chronic obstructive pulmonary disease (COPD) is primarily caused by inhalation of cigarette smoke and is the third leading cause of death worldwide. Pulmonary surfactant, a complex of phospholipids and proteins, plays an essential role in respiration by reducing the surface tension in the alveoli. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is an enzyme that catalyzes the biosynthesis of surfactant lipids and is expressed in type 2 alveolar epithelial cells. Its dysfunction is suggested to be involved in various lung diseases; however, the relationship between LPCAT1 and COPD remains unclear. To investigate the role of LPCAT1 in the pathology of COPD, we analyzed an elastase-induced emphysema model using Lpcat1 knockout (KO) mice. In Lpcat1 KO mice, elastase-induced emphysema was significantly exacerbated with increased apoptotic cells, which was not ameliorated by supplementation with dipalmitoylphosphatidylcholine, which is a major component of the surfactant synthesized by LPCAT1. We subsequently evaluated the effects of cigarette smoking on primary human type 2 alveolar epithelial cells (hAEC2s) and found that cigarette smoke extract (CSE) downregulated the expression of Lpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression of Lpcat1 using small interfering RNA, which resulted in enhanced CSE-induced apoptosis in A549 cells. Taken together, cigarette smoke–induced downregulation of LPCAT1 can promote the exacerbation of pulmonary emphysema by increasing the susceptibility of alveolar epithelial cells to apoptosis, thereby suggesting that Lpcat1 is a novel therapeutic target for irreversible emphysema.

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One-year follow-up CT findings in COVID-19 patients: A systematic review and meta-analysis

Watanabe A., So M., Iwagami M., Fukunaga K., Takagi H., Kabata H., Kuno T.

Respirology 27 （ 8 ） 605 - 616 2022年08月

ISSN 13237799

Coronavirus disease 2019 (COVID-19) often causes radiological and functional pulmonary sequelae. However, evidence on 1-year follow-up of pulmonary sequelae is limited. We aimed to investigate the characteristics and time-course of pulmonary sequelae after recovery from COVID-19 through 1-year follow-up. We searched PubMed and EMBASE databases on 25 February 2022, and included studies with computed tomography (CT) findings at the 1-year follow-up. The extracted data on CT findings were analysed using a one-group meta-analysis. We further analysed the data in relation to COVID-19 severity, improvement rate and lung function. Fifteen eligible studies (N = 3134) were included. One year after COVID-19, 32.6% (95% CI 24.0–42.6, I2 = 92.9%) presented with residual CT abnormalities. Ground-glass opacity and fibrotic-like changes were frequently observed in 21.2% (95% CI 15.4–28.4, I2 = 86.7%) and 20.6% (95% CI 11.0–35.2, I2 = 91.9%), respectively. While the gradual recovery was seen on CT (52.9% [mid-term] vs. 32.6% [1 year]), the frequency of CT abnormalities was higher in the severe/critical cases than in the mild/moderate cases (37.7% vs. 20.7%). In particular, fibrotic changes showed little improvement between 4–7 months and 1 year after COVID-19. Pulmonary function tests at 1 year also showed the decline in diffusing capacity of the lung for carbon monoxide, especially in severe/critical cases. Our meta-analysis indicated that residual CT abnormalities were common in hospitalized COVID-19 patients 1 year after recovery, especially fibrotic changes in severe/critical cases. As these sequelae may last long, vigilant observations and longer follow-up periods are warranted.

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Young woman with multiple lung nodules: a pulmonary oxymoron

Tanaka H., Kabata H., Emoto K., Hayashi S., Masai K., Fukunaga K.

Thorax 77 （ 11 ） 1155 - 1157 2022年07月

ISSN 00406376

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Heterogeneity of ILC2s in the Lungs

Asaoka M., Kabata H., Fukunaga K.

Frontiers in Immunology 13 2022年06月

Group 2 innate lymphoid cells (ILC2s) are GATA3-expressing type 2 cytokine-producing innate lymphocytes that are present in various organs throughout the body. Basically, ILC2s are tissue-resident cells associated with a variety of pathological conditions in each tissue. Differences in the tissue-specific properties of ILC2s are formed by the post-natal tissue environment; however, diversity exists among ILC2s within each localized tissue due to developmental timing and activation. Diversity between steady-state and activated ILC2s in mice and humans has been gradually clarified with the advancement of single-cell RNA-seq technology. Another layer of complexity is that ILC2s can acquire other ILC-like functions, depending on their tissue environment. Further, ILC2s with immunological memory and exhausted ILC2s are both present in tissues, and the nature of ILC2s varies with senescence. To clarify how ILC2s affect human diseases, research should be conducted with a comprehensive understanding of ILC2s, taking into consideration the diversity of ILC2s rather than a snapshot of a single section. In this review, we summarize the current understanding of the heterogeneity of ILC2s in the lungs and highlight a novel field of immunology.

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Immune evasion and chronological decrease in titer of neutralizing antibody against SARS-CoV-2 and its variants of concerns in COVID-19 patients

Takeshita M., Nishina N., Moriyama S., Takahashi Y., Ishii M., Saya H., Kondo Y., Kaneko Y., Suzuki K., Fukunaga K., Takeuchi T.

Clinical Immunology 238 2022年05月

ISSN 15216616

Many variants of SARS-CoV-2 have emerged, and decreased neutralizing antibodies after vaccination and breakthrough infections have become a problem. The importance of monitoring titers of neutralizing antibodies is getting higher. We enrolled 146 COVID-19 patients, who were thought to be infected with Wuhan-hu-1 or D614G strains, and examined the time course of neutralizing titers against six concerning strains (Wuhan-hu-1, Alpha, Beta, Gamma, Kappa, and Delta) using newly developed ELISA. The acquisition of neutralizing titer was positively associated with disease severity. Immune evasions were observed approximately 20 to 30% for Alpha, Kappa, and Delta variant, and 40 to 45% for Beta and Gamma variant. The titers against all strains decreased over time, and interestingly, while titers against Wuhan-hu-1 decreased by 23%, those to Delta variant decreased by 70%. Our simple, cost-effective, and non-hazardous system will be applicable to process numerous samples, such as monitoring titers against prevalent strains after infection or vaccination.

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Clinical Utility of the Electrocardiographic P-Wave Axis in Patients with Chronic Obstructive Pulmonary Disease

Otake S., Chubachi S., Nakayama S., Sakurai K., Irie H., Hashiguchi M., Itabashi Y., Yamada Y., Jinzaki M., Murata M., Nakamura H., Asano K., Fukunaga K.

Respiration 101 （ 4 ） 345 - 352 2022年04月

ISSN 00257931

Background: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated. Methods: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years. We analyzed 201 patients using ECG and chest computed tomography. Results: The severity of airflow limitation was higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. Patients with a P-wave axis >75° exhibited significantly higher total COPD assessment test scores and increased St. George's Respiratory Questionnaire total, activity, and impact scores than those with a P-wave axis ≤75°. The incidence of exacerbations over 1 and 3 years was significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. The optimal cutoff for the P-wave axis for a percentage of the predicted forced expiratory volume in 1 s <50% and future exacerbations over 3 years was 70° (the areas under the curve [AUC]: 0.788; sensitivity: 65.3%; specificity: 78.3%) and 79° (AUC: 0.642; sensitivity: 36.7%; specificity: 92.6%). The ratio of the low attenuation area was also significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. However, the ratio of the airway wall area did not differ between the 2 groups. Conclusions: Patients with COPD with a vertical P-wave axis exhibited severe airflow limitation and emphysema, a worse health status, and more frequent exacerbation than patients without a vertical P-wave. Detection of the vertical P-wave axis by ECG is beneficial for the management of patients with COPD.

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A 70-Year-Old Woman With Long-Term Nonresolving Pneumonia

Tomiyasu S., Kabata H., Emoto K., Azekawa S., Maeda C., Masai K., Yasuda H., Fukunaga K.

Chest 161 （ 4 ） e219 - e223 2022年04月

ISSN 00123692

Case Presentation: A 70-year-old woman who had received a diagnosis of pneumonia in the right lower lobe was treated with antibiotics at a general practitioner's clinic 9 months earlier. Her pneumonia had improved, but the cough and lung infiltrates persisted for > 6 months, so the patient was referred to our hospital. She had undergone surgery for breast cancer 30 years earlier but had no other medical history. She was not taking any medications and had no history of smoking, including passive smoking.

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Apixaban-Associated Diffuse Alveolar Hemorrhage in an Elderly Man with Multiple Complications

Ozawa T., Terai H., Kajino A., Otake S., Saito A., Nishie M., Kishino Y., Kamata H., Hayashida K., Ishii M., Fukunaga K.

American Journal of Case Reports 23 （ 1 ） 2022年

Objective: Background: Case Report: Conclusions: Unusual clinical course Diffuse alveolar hemorrhage (DAH) caused by direct oral anticoagulants (DOACs) has increased in recent years with the increase in prescriptions of DOACs. Generally, DOACs are considered to have a lower bleeding risk than the traditional anticoagulant, warfarin. However, major bleeding, including DAH, due to DOACs can be seen in clinical practice, and there are few reports to elucidate when DOAC-associated alveolar hemorrhage occurs and whether DOAC-induced DAH has a trigger. An 80-year-old man diagnosed and treated for atrial fibrillation with apixaban 2.5 mg twice daily for 1 year before admission, underwent 2 invasive medical procedures over a short period of time. Hemoptysis began after the procedures. He experienced shortness of breath and rapidly progressive hypoxic respiratory failure. His postsurgical oxygen saturation level dropped rapidly. Chest radiography and computed tomography images showed pulmonary infiltration and ground-glass opacity in both lungs. Apixaban treatment was discontinued, and mechanical ventilation was initiated. Bronchoalveolar lavage cytology revealed hemosiderin-laden macrophages. A diagnosis of diffuse alveolar hemorrhage (DAH) was made. In previous reports about DAH caused by DOACs, most patients had bleeding triggers; drug interactions in patients taking DOACs are one of such triggers. Although DOACs are relatively safe for elderly patients, DAH can occur in patients receiving either earlystage or long-term treatment. The onset of DOAC-associated DAH is not limited to the early stages of medication initiation. Various triggers can induce DAH in patients receiving DOACs.

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Diagnostic Performance of Computed Tomography Imaging for COVID-19 in a Region with Low Disease Prevalence

Lee H., Suzuki T., Okada Y., Tanaka H., Okamori S., Kamata H., Ishii M., Jinzaki M., Fukunaga K.

Keio Journal of Medicine 71 （ 1 ） 21 - 30 2022年

ISSN 00229717

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019 as an outbreak of pneumonia of unknown origin. Previous studies have suggested the utility of chest computed tomography (CT) in the diagnosis of COVID-19 because of its high sensitivity (93%–97%), relatively simple procedure, and rapid test results. This study, performed in Japan early in the epidemic when COVID-19 prevalence was low, evaluated the diagnostic accuracy of chest CT in a population presenting with lung diseases having CT findings similar to those of COVID-19. We retrospectively included all consecutive patients (≥18 years old) presenting to the outpatient department of Keio University Hospital between March 1 and May 31, 2020, with fever and respiratory symptoms. We evaluated the performance of diagnostic CT for COVID-19 by using polymerase chain reaction (PCR) results as the reference standard. We determined the numbers of false-positive (FP) results and assessed the clinical utility using decision curve analysis. Of the 175 patients, 22 were PCR-positive. CT had a sensitivity of 68% and a specificity of 57%. Patients with FP results on CT diagnosis were mainly diagnosed with diseases mimicking COVID-19, e.g., interstitial lung disease. Decision curve analysis indicated that the clinical utility of CT imaging was limited. The diagnostic performance of CT for COVID-19 was inadequate in an area with low COVID-19 prevalence and a high prevalence of other lung diseases with chest CT findings similar to those of COVID-19. Considering this insufficient diagnostic performance, CT findings should be evaluated in the context of additional medical information to diagnose COVID-19.

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Development of Rheumatoid Arthritis in Cavitary Mycobacterium avium Pulmonary Disease: A Case Report of Successful Treatment with CTLA4-Ig (Abatacept)

Tanaka H., Asakura T., Kikuchi J., Ishii M., Namkoong H., Kaneko Y., Fukunaga K., Hasegawa N.

Infection and Drug Resistance 15 91 - 97 2022年

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently admi-nistered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

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Early-Phase Adverse Effects and Management of Liposomal Amikacin Inhalation for Refractory Mycobacterium avium Complex Lung Disease in Real-World Settings

Morita A., Namkoong H., Yagi K., Asakura T., Hosoya M., Tanaka H., Lee H., Ogawa T., Kusumoto T., Azekawa S., Nakagawara K., Kamata H., Ishii M., Fukunaga K., Ozawa H., Hasegawa N.

Infection and Drug Resistance 15 4001 - 4011 2022年

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

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