Papers - Fukunaga, Koichi

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

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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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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

ISSN  00229717

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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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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature 600 ( 7889 ) 472 - 477 2021.12

ISSN  00280836

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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study

Ikeda S., Misumi T., Izumi S., Sakamoto K., Nishimura N., Ro S., Fukunaga K., Okamori S., Tachikawa N., Miyata N., Shinkai M., Shinoda M., Miyazaki Y., Iijima Y., Izumo T., Inomata M., Okamoto M., Yamaguchi T., Iwabuchi K., Masuda M., Takoi H., Oyamada Y., Fujitani S., Mineshita M., Ishii H., Nakagawa A., Yamaguchi N., Hibino M., Tsushima K., Nagai T., Ishikawa S., Ishikawa N., Kondoh Y., Yamazaki Y., Gocho K., Nishizawa T., Tsuzuku A., Yagi K., Shindo Y., Takeda Y., Yamanaka T., Ogura T.

Scientific Reports 11 ( 1 )  2021.12

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Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841–2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347–5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation. Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).

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Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19

Tanaka H., Lee H., Morita A., Namkoong H., Chubachi S., Kabata H., 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., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

International Journal of Infectious Diseases 113   74 - 81 2021.12

ISSN  12019712

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Background and design:: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. Results:: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45–71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. Conclusions:: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

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Characteristics of chronic obstructive pulmonary disease patients with robust progression of emphysematous change

Tsutsumi A., Chubachi S., Irie H., Sasaki M., Yamada Y., Sugiura H., Jinzaki M., Nakamura H., Asano K., Betsuyaku T., Fukunaga K.

Scientific Reports 11 ( 1 )  2021.12

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Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P = 0.04) and having osteoporosis (OR, 2.13; P = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.

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Differences in airway lumen area between supine and upright computed tomography in patients with chronic obstructive pulmonary disease

Chubachi S., Yamada Y., Yamada M., Yokoyama Y., Tanabe A., Matsuoka S., Niijima Y., Yamasawa W., Irie H., Murata M., Fukunaga K., Jinzaki M.

Respiratory Research 22 ( 1 )  2021.12

ISSN  14659921

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Background: No clinical studies to date have compared the inspiratory and expiratory airway lumen area between supine and standing positions. Thus, the aims of this study were twofold: (1) to compare inspiratory and expiratory airway lumen area (IAA and EAA, respectively) on computed tomography (CT) among supine and standing positions; and (2) to investigate if IAA and EAA are associated with lung function abnormality in patients with chronic obstructive pulmonary disease (COPD). Methods: Forty-eight patients with COPD underwent both low-dose conventional (supine position) and upright CT (standing position) during inspiration and expiration breath-holds and a pulmonary function test (PFT) on the same day. We measured the IAA and EAA in each position. Results: For the trachea to the third-generation bronchi, the IAA was significantly larger in the standing position than in the supine position (4.1–4.9% increase, all p < 0.05). The EAA of all bronchi was significantly larger in the standing position than in the supine position (9.7–62.5% increases, all p < 0.001). The correlation coefficients of IAA in the standing position and forced expiratory volume in 1 s were slightly higher than those in the supine position. The correlation coefficients of EAA or EAA/IAA in the standing position and residual volume, and the inspiratory capacity/total lung capacity ratio were higher than those in the supine position. Conclusions: Airway lumen areas were larger in the standing position than in the supine position. IAAs reflect airway obstruction, and EAAs reflect lung hyperinflation. Upright CT might reveal these abnormalities more precisely. Trial registration University Hospital Medical Information Network (UMIN 000026587), Registered 17 March 2017. URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000030456.

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Radiological and functional lung sequelae of COVID-19: a systematic review and meta-analysis

So M., Kabata H., Fukunaga K., Takagi H., Kuno T.

BMC Pulmonary Medicine 21 ( 1 )  2021.12

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Background: The coronavirus disease 2019 (COVID-19) causes a wide spectrum of lung manifestations ranging from mild asymptomatic disease to severe respiratory failure. We aimed to clarify the characteristics of radiological and functional lung sequelae of COVID-19 patients described in follow-up period. Method: PubMed and EMBASE were searched on January 20th, 2021 to investigate characteristics of lung sequelae in COVID-19 patients. Chest computed tomography (CT) and pulmonary function test (PFT) data were collected and analyzed using one-group meta-analysis. Results: Our search identified 15 eligible studies with follow-up period in a range of 1–6 months. A total of 3066 discharged patients were included in these studies. Among them, 1232 and 1359 patients were evaluated by chest CT and PFT, respectively. The approximate follow-up timing on average was 90 days after either symptom onset or hospital discharge. The frequency of residual CT abnormalities after hospital discharge was 55.7% (95% confidential interval (CI) 41.2–70.1, I2 = 96.2%). The most frequent chest CT abnormality was ground glass opacity in 44.1% (95% CI 30.5–57.8, I2 = 96.2%), followed by parenchymal band or fibrous stripe in 33.9% (95% CI 18.4–49.4, I2 = 95.0%). The frequency of abnormal pulmonary function test was 44.3% (95% CI 32.2–56.4, I2 = 82.1%), and impaired diffusion capacity was the most frequently observed finding in 34.8% (95% CI 25.8–43.8, I2 = 91.5%). Restrictive and obstructive patterns were observed in 16.4% (95% CI 8.9–23.9, I2 = 89.8%) and 7.7% (95% CI 4.2–11.2, I2 = 62.0%), respectively. Conclusions: This systematic review suggested that about half of the patients with COVID-19 still had residual abnormalities on chest CT and PFT at about 3 months. Further studies with longer follow-up term are warranted.

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PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment

Takehara T., Wakamatsu E., Machiyama H., Nishi W., Emoto K., Azuma M., Soejima K., Fukunaga K., Yokosuka T.

Communications Biology 4 ( 1 )  2021.12

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The coinhibitory receptor, PD-1, is of major importance for the suppression of T cell activation in various types of immune responses. A high-resolution imaging study showed that PD-1 forms a coinhibitory signalosome, “PD-1 microcluster”, with the phosphatase, SHP2, to dephosphorylate the TCR/CD3 complex and its downstream signaling molecules. Such a consecutive reaction entirely depended on PD-1–PD-L1/2 binding. PD-L2 is expressed on professional antigen-presenting cells and also on some tumor cells, which possibly explains the discrepant efficacy of immune checkpoint therapy for PD-L1-negative tumors. Here, we performed precise imaging analysis of PD-L2 forming PD-1–PD-L2 clusters associating with SHP2. PD-L2 could compete with PD-L1 for binding to PD-1, occupying the same space at TCR microclusters. The PD-1 microcluster formation was inhibited by certain mAbs with functional consequences. Thus, PD-1 microcluster formation provides a visible index for the effectiveness of anti-PD-1- or anti-PD-L1/2-mediated T cell suppression. PD-L2 may exert immune suppressive responses cooperatively with PD-L1 on the microcluster scale.

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Longitudinal Assessment of Prognostic Understanding in Patients with Advanced Lung Cancer and Its Association with Their Psychological Distress

Arai D., Sato T., Nakachi I., Fujisawa D., Takeuchi M., Sato Y., Kawada I., Yasuda H., Ikemura S., Terai H., Nukaga S., Inoue T., Nakamura M., Oyamada Y., Terashima T., Sayama K., Saito F., Sakamaki F., Naoki K., Fukunaga K., Soejima K.

Oncologist 26 ( 12 ) e2265 - e2273 2021.12

ISSN  10837159

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Background: Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time. Materials and Methods: We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being. Results: The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p =.010 and p =.014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer–specific symptom burden at 3 months (p =.008 and p =.005, respectively) and lower emotional well-being at 6 months (p =.006). Conclusion: Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately. Implications for Practice: This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.

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Finding of the factors affecting the severity of COVID-19 based on mathematical models

Qu J., Sumali B., Lee H., Terai H., Ishii M., Fukunaga K., Mitsukura Y., Nishimura T.

Scientific Reports 11 ( 1 )  2021.12

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Since 2019, a large number of people worldwide have been infected with severe acute respiratory syndrome coronavirus 2. Among those infected, a limited number develop severe coronavirus disease 2019 (COVID-19), which generally has an acute onset. The treatment of patients with severe COVID-19 is challenging. To optimize disease prognosis and effectively utilize medical resources, proactive measures must be adopted for patients at risk of developing severe COVID-19. We analyzed the data of COVID-19 patients from seven medical institutions in Tokyo and used mathematical modeling of patient blood test results to quantify and compare the predictive ability of multiple prognostic indicators for the development of severe COVID-19. A machine learning logistic regression model was used to analyze the blood test results of 300 patients. Due to the limited data set, the size of the training group was constantly adjusted to ensure that the results of machine learning were effective (e.g., recognition rate of disease severity > 80%). Lymphocyte count, hemoglobin, and ferritin levels were the best prognostic indicators of severe COVID-19. The mathematical model developed in this study enables prediction and classification of COVID-19 severity.

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: Study protocol

Nakagawara K., Namkoong H., Terai H., Masaki K., Tanosaki T., Shimamoto K., Lee H., Tanaka H., Okamori S., Kabata H., Chubachi S., Ikemura S., Kamata H., Yasuda H., Kawada I., Ishii M., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Kagyo J., Shiomi T., Ohgino K., Sayama K., Otsuka K., Miyao N., Odani T., Oyamada Y., Masuzawa K., Nakayama S., Suzuki Y., Baba R., Nakachi I., Kuwahara N., Ishiguro T., Mashimo S., Minematsu N., Ueda S., Manabe T., Funatsu Y., Koh H., Yoshiyama T., Saito F., Ishioka K., Takahashi S., Nakamura M., Goto A., Harada N., Kusaka Y., Nakano Y., Nishio K., Tateno H., Edahiro R., Takeda Y., Kumanogoh A., Kodama N., Okamoto M., Umeda A., Hagimura K., Sato T., Miyazaki N., Takemura R., Sato Y., Takebayashi T., Nakahara J., Mimura M., Ogawa K., Shimmura S., Negishi K., Tsubota K., Amagai M., Goto R., Ibuka Y., Hasegawa N., Kitagawa Y., Kanai T., Fukunaga K.

BMJ Open Respiratory Research 8 ( 1 )  2021.11

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Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

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ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population

Okamori S., Ishii M., Asakura T., Suzuki S., Namkoong H., Kagawa S., Hegab A.E., Yagi K., Kamata H., Kusumoto T., Ogawa T., Takahashi H., Yoda M., Horiuchi K., Hasegawa N., Fukunaga K.

American Journal of Physiology - Lung Cellular and Molecular Physiology 321 ( 5 ) L872 - L884 2021.11

ISSN  10400605

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The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10DLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10DLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10DLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10DLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10DLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

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Difference in the airway luminal area between the standing and supine positions using upright and conventional computed tomography

Matsumoto S., Yamada Y., Yamada M., Chubachi S., Yokoyama Y., Matsuoka S., Tanabe A., Niijima Y., Murata M., Fukunaga K., Jinzaki M.

Clinical Anatomy 34 ( 8 ) 1150 - 1156 2021.11

ISSN  08973806

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No clinical studies to date have compared the airway luminal area between supine and standing positions. Our aim was therefore to compare the airway luminal area between these two positions on computed tomography (CT) and to determine its correlation with forced expiratory volume in 1 s (FEV1). Thirty-two asymptomatic volunteers underwent both conventional (supine position) and upright (standing position) CT during deep inspiration breath-holding. Pulmonary function tests were conducted on the same day. We measured the airway luminal area on CT in each position. Paired t-tests and Pearson's correlation coefficients were used for statistical analysis. The average luminal areas of the trachea, right and left main bronchi, and average third-generation airway were greater in the standing than the supine position by 3.4%, 6.1%, 5.5%, and 5.2%, respectively. The correlation coefficients between airway luminal areas and FEV1 tended to be higher in the standing than the supine position; this correlation was highest for the average third-generation airway (r = 0.70, P < 0.0001). The airway luminal areas of the trachea, bilateral main bronchi, and average third-generation airway were greater in the standing than the supine position. The average third-generation airway area in the standing position had the highest correlation with FEV1.

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The effect of the outbreak of COVID-19 on respiratory physicians and healthcare in Japan: Serial nationwide surveys by the Japanese Respiratory Society

Kamada K., Konno S., Kaneko T., Fukunaga K., Hasegawa Y., Yokoyama A.

Respiratory Investigation 59 ( 6 ) 792 - 798 2021.11

ISSN  22125345

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Background: The impact of the outbreak of COVID-19 on the work of respiratory physicians in Japan has not yet been evaluated. The study investigates the impact of the outbreak on respiratory physicians’ work over time and identifies problems to be addressed in the future. Methods: We conducted a web-based survey of respiratory physicians in 848 institutions. The survey comprised 32 questions and four sections: Survey 1 (April 20, 2020), Survey 2 (May 27, 2020), Survey 3 (August 31, 2020), and Survey 4 (December 4, 2020). Results: The mean survey response rate was 24.9%, and 502 facilities (59.2%) participated in at least one survey. The proportion of facilities that could perform PCR tests for diagnosis and more than 20 tests per day gradually increased. The percentage capable of managing extracorporeal membrane oxygenation (ECMO) or more than five ventilators did not increase over time. The proportion that reported work overload of 150% or more, stress associated with lack of personal protective equipment (PPE), and harassment or stigma in the surrounding community did not sufficiently improve. Conclusion: While there was an improvement in expanding the examination system and medical cooperation in the community, there was no indication of enhancement of the critical care management system. The overwork of respiratory physicians, lack of PPE, and harassment and stigma related to COVID-19 did not sufficiently improve and need to be addressed urgently.

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Cardiac tamponade due to primary malignant pericardial mesothelioma diagnosed with surgical pericardial resection

Kawakami N., Kawai M., Namkoong H., Arai D., Ueda S., Hamada K., Kawada I., Hasegawa N., Mikami S., Asamura H., Fukunaga K.

Journal of Cardiology Cases 24 ( 4 ) 149 - 152 2021.10

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Primary malignant pericardial mesothelioma is an extremely rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. A 67-year-old male patient, an ex-smoker, complaining of progressive lethargy was referred to a hospital for investigation of persistent pericardial effusion. The pericardial fluid cytology was categorized as class Ⅲ. Thereafter, he was referred to our hospital for further evaluation. Fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed FDG accumulation in the pericardium and mediastinal lymph node. Surgical biopsy of the pericardium was performed through a subxiphoid approach for a definitive diagnosis. Histopathological examination revealed diffuse infiltration of the pericardium by a malignant tumor consisting of epithelioid cells with large round nuclei and prominent nucleoli, arranged in a tubular papillary pattern. Finally, the patient was diagnosed with primary malignant pericardial mesothelioma of epithelioid type. The patient died 6 weeks after admission. This diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and FDG PET to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit. <Learning objective: Primary malignant pericardial mesothelioma is a rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. However, this diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and fluorodeoxyglucose positron emission tomography to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit.>

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Nasal delivery of single-domain antibody improves symptoms of SARS-CoV-2 infection in an animal model

Haga K., Takai-Todaka R., Matsumura Y., Song C., Takano T., Tojo T., Nagami A., Ishida Y., Masaki H., Tsuchiya M., Ebisudani T., Sugimoto S., Sato T., Yasuda H., Fukunaga K., Sawada A., Nemoto N., Murata K., Morimoto T., Katayama K.

PLoS Pathogens 17 ( 10 )  2021.10

ISSN  15537366

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.

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Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice

Hegab A.E., Ozaki M., Kagawa S., Fukunaga K.

Stem Cells and Development 30 ( 18 ) 908 - 921 2021.09

ISSN  15473287

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Lung fibrosis is a progressive fatal disease, and the underlying mechanisms remain unclear. These involve a combination of altered fibroblasts, excessive accumulation of extracellular matrix, inflammation, and aberrant activation of epithelial cells. Previously, we showed that high-fat diet (HFD) induces lung inflammation, aberrant activation of stem cells, and lung mitochondria impairment. Therefore, we hypothesized that HFD-induced changes would influence lung fibrosis. Mice were fed standard diet (SD) or HFD, administered bleomycin, then examined for fibrosis severity and the start of repair 3 weeks after injury, and for fibrosis repair/resolution 6-9 weeks after injury. At 3 weeks, no significant differences in inflammation and fibrosis severity were observed between SD-and HFD-fed mice. However, infiltration of alveolar type (AT)-2 cells and bronchioalveolar stem cells (BASCs) into the fibrotic areas (the start of repair) was impaired in HFD-fed mice. At 6 weeks, SD-fed mice showed near-complete resolution/repair of fibrosis and inflammation, while HFD-fed mice still showed residual fibrosis and inflammation. Infiltration of the fibrotic areas with AT2 cells was observed, but very few BASCs were detectable. At 9 weeks, mice from both groups showed complete resolution/repair of fibrosis and inflammation, indicating that HFD induced delayed, rather than failed, resolution of fibrosis and alveolar repair. To further confirm the direct role of enhanced fatty-acid oxidation (FAO) in delayed resolution/repair, we administered etomoxir, a FAO inhibitor, to HFD-fed mice for 3-6 weeks after bleomycin injury. Inhibition of FAO abolished the HFD-induced delay in alveolar repair and fibrosis resolution at both time points. In conclusion, after a fibrosis-inducing injury, HFD slows resolution of fibrosis/inflammation and delays alveolar repair by slowing the contribution of AT2 stem cells and abolishing the contribution of BASCs in the repair process. FAO activation appears to be involved in this delay mechanism; thus, inhibiting FAO may be useful in the treatment of lung injury and fibrosis.

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TLR7 agonist suppresses group 2 innate lymphoid cell–mediated inflammation via IL-27–producing interstitial macrophages

Okuzumi S., Miyata J., Kabata H., Mochimaru T., Kagawa S., Masaki K., Irie M., Morita H., Fukunaga K.

American Journal of Respiratory Cell and Molecular Biology 65 ( 3 ) 309 - 318 2021.09

ISSN  10441549

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Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33–induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33–induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33–induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1–deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33–induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.

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Clinical Features and Prognosis of Nontuberculous Mycobacterial Pleuritis

Yagi K., Ito A., Fujiwara K., Morino E., Hase I., Nakano Y., Asakura T., Furuuchi K., Morita A., Asami T., Namkoong H., Saito F., Morimoto K., Ishii M., Sato Y., Tateno H., Nishio K., Oyamada Y., Fukunaga K., Sugiyama H., Ishida T., Kurashima A., Hasegawa N.

Annals of the American Thoracic Society 18 ( 9 ) 1490 - 1497 2021.09

ISSN  23296933

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Rationale: The clinical features and prognosis of nontuberculous mycobacterial (NTM) pleuritis and pleural effusion combined with NTM lung disease remain unclear. Objectives: To investigate the clinical features and prognosis of NTM pleuritis. Methods: This retrospective observational study included patients with NTM pleuritis from January 2001 to June 2018 across eight hospitals in Japan. NTM pleuritis was defined by a positive NTM culture of pleural effusion samples. We matched patients with Mycobacterium avium complex (MAC) lung disease (MAC-LD) without pleuritis by sex and age to obtain comparative data and investigated the association between clinical parameters and the prognosis. Results: We identified 64 patients with NTM pleuritis (median age, 73 yr; 37 female patients). The median follow-up duration was 11 months, and 27 patients died. Patients with MAC pleuritis had a significantly lower survival rate than matched patients with MAC-LD without pleuritis. Multivariate analysis revealed that pleuritis (adjusted hazard ratio, 6.99; 95% confidence interval [CI], 2.58–19.00) and underlying pulmonary diseases (adjusted hazard ratio, 3.01; 95% CI, 1.44–6.28) were independently associated with all-cause mortality in patients with MAC-LD. Conclusions: The prognosis of MAC pleuritis is poorer than that of MAC-LD without pleuritis. Pleuritis is an independent prognostic factor in patients with MAC-LD.

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