Details of a Researcher - Fukunaga, Koichi

Papers - Fukunaga, Koichi

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Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study

Okada M., Ishida N., Kanzaki S., Kawada I., Nagashima K., Terai H., Hiruma G., Namkoong H., Asakura T., Masaki K., Ohgino K., Miyata J., Chubachi S., Kodama N., Maeda S., Sakamoto S., Okamoto M., Nagasaki Y., Umeda A., Miyagawa K., Shimada H., Minami K., Hagiwara R., Ishii M., Sato Y., Fukunaga K.

OTO Open 8 ( 1 ) 2024.01

Objective: This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design: Prospective cohort study. Setting: A multicenter study involving 26 medical facilities in Japan. Methods: Inclusion criteria were patients aged ≥18 years old with a confirmed COVID-19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient-reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results: Patients with high albumin, low C-reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282-6.526) for taste disorders and 3.534 (95% CI, 1.382-9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion: The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID-19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

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Current advances in pulmonary functional imaging

Nakamura H., Hirai T., Kurosawa H., Hamada K., Matsunaga K., Shimizu K., Konno S., Muro S., Fukunaga K., Nakano Y., Kuwahira I., Hanaoka M.

Respiratory Investigation 62 ( 1 ) 49 - 65 2024.01

ISSN 22125345

Recent advances in imaging analysis have enabled evaluation of ventilation and perfusion in specific regions by chest computed tomography (CT) and magnetic resonance imaging (MRI), in addition to modalities including dynamic chest radiography, scintigraphy, positron emission tomography (PET), ultrasound, and electrical impedance tomography (EIT). In this review, an overview of current functional imaging techniques is provided for each modality. Advances in chest CT have allowed for the analysis of local volume changes and small airway disease in addition to emphysema, using the Jacobian determinant and parametric response mapping with inspiratory and expiratory images. Airway analysis can reveal characteristics of airway lesions in chronic obstructive pulmonary disease (COPD) and bronchial asthma, and the contribution of dysanapsis to obstructive diseases. Chest CT is also employed to measure pulmonary blood vessels, interstitial lung abnormalities, and mediastinal and chest wall components including skeletal muscle and bone. Dynamic CT can visualize lung deformation in respective portions. Pulmonary MRI has been developed for the estimation of lung ventilation and perfusion, mainly using hyperpolarized 129Xe. Oxygen-enhanced and proton-based MRI, without a polarizer, has potential clinical applications. Dynamic chest radiography is gaining traction in Japan for ventilation and perfusion analysis. Single photon emission CT can be used to assess ventilation-perfusion (V˙/Q˙) mismatch in pulmonary vascular diseases and COPD. PET/CT V˙/Q˙ imaging has also been demonstrated using “Galligas”. Both ultrasound and EIT can detect pulmonary edema caused by acute respiratory distress syndrome. Familiarity with these functional imaging techniques will enable clinicians to utilize these systems in clinical practice.

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Clinical characteristics of allergic bronchopulmonary mycosis caused by Schizophyllum commune

Oguma T., Ishiguro T., Kamei K., Tanaka J., Suzuki J., Hebisawa A., Obase Y., Mukae H., Tanosaki T., Furusho S., Kurokawa K., Watai K., Matsuse H., Harada N., Nakamura A., Shibayama T., Baba R., Fukunaga K., Matsumoto H., Ohba H., Sakamoto S., Suzuki S., Tanaka S., Yamada T., Yamasaki A., Fukutomi Y., Shiraishi Y., Toyotome T., Fukunaga K., Shimoda T., Konno S., Taniguchi M., Tomomatsu K., Okada N., Asano K.

Clinical and Translational Allergy 14 ( 1 ) 2024.01

Background: Allergic bronchopulmonary mycosis (ABPM) is an allergic disease caused by type I and type III hypersensitivity to environmental fungi. Schizophyllum commune, a basidiomycete fungus, is one of the most common fungi that causes non-Aspergillus ABPM. Objective: Herein, we attempted to clarify the clinical characteristics of ABPM caused by S. commune (ABPM-Sc) compared with those of allergic bronchopulmonary aspergillosis (ABPA). Methods: Patients with ABPM-Sc or ABPA were recruited from a nationwide survey in Japan, a multicenter cohort, and a fungal database at the Medical Mycology Research Center of Chiba University. The definition of culture-positive ABPM-Sc/ABPA is as follows: (1) fulfills five or more of the 10 diagnostic criteria for ABPM proposed by Asano et al., and (2) positive culture of S. commune/Aspergillus spp. in sputum, bronchial lavage fluid, or mucus plugs in the bronchi. Results: Thirty patients with ABPM-Sc and 46 with ABPA were recruited. Patients with ABPM-Sc exhibited less severe asthma and presented with better pulmonary function than those with ABPA (p = 0.008–0.03). Central bronchiectasis was more common in ABPM-Sc than that in ABPA, whereas peripheral lung lesions, including infiltrates/ground-glass opacities or fibrotic/cystic changes, were less frequent in ABPM-Sc. Aspergillus fumigatus-specific immunoglobulin (Ig)E was negative in 10 patients (34%) with ABPM-Sc, who demonstrated a lower prevalence of asthma and levels of total serum IgE than those with ABPM-Sc positive for A. fumigatus-specific IgE or ABPA. Conclusions: Clinical characteristics of ABPM-Sc, especially those negative for A. fumigatus-specific IgE, differed from those of ABPA.

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Epicardial adipose tissue measured from analysis of adipose tissue area using chest CT imaging is the best potential predictor of COVID-19 severity

Fukushima T., Maetani T., Chubachi S., Tanabe N., Asakura T., Namkoong H., Tanaka H., Shimada T., Azekawa S., Otake S., Nakagawara K., Watase M., Shiraishi Y., Terai H., Sasaki M., Ueda S., Kato Y., Harada N., Suzuki S., Yoshida S., Tateno H., Yamada Y., Jinzaki M., Hirai T., Okada Y., Koike R., Ishii M., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Metabolism: Clinical and Experimental 150 2024.01

ISSN 00260495

Background: Computed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue. Aim: The purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient database, we analyzed the associations of chest subcutaneous, chest visceral, abdominal subcutaneous, and Abd-VAT areas with COVID-19 outcomes. In addition, the clinical significance of central obesity, commonly disregarded by BMI, was examined. Methods: This retrospective cohort study evaluated patients with COVID-19 aged ≥18 years In Japan. Data including from chest CT images collected between February 2020 and October 2022 in four hospitals of the Japan COVID-19 Task Force were analyzed. Patient characteristics and COVID-19 severity were compared according to the adipose tissue areas (chest and abdominal subcutaneous adipose tissue [Chest-SAT and Abd-SAT], EAT, and Abd-VAT) calculated from chest CT images. Results: We included 1077 patients in the analysis. Patients with risk factors of severe COVID-19 such as old age, male sex, and comorbidities had significantly higher areas of EAT and Abd-VAT. High EAT area but not high Abd-VAT area was significantly associated with COVID-19 severity (adjusted odds ratio (aOR): 2.66, 95 % confidence interval [CI]: 1.19–5.93). There was no strong correlation between BMI and VAT. Patients with high VAT area accounted for 40.7 % of the non-obesity population (BMI < 25 kg/m2). High EAT area was also significantly associated with COVID-19 severity in the non-obesity population (aOR: 2.50, 95 % CI: 1.17–5.34). Conclusions: Our study indicated that VAT is significantly associated with COVID-19 severity and that EAT is the best potential predictor for risk stratification in COVID-19 among adipose tissue areas. Body composition assessment using EAT is an appropriate marker for identifying obesity patients overlooked by BMI. Considering the next pandemic of the global health crisis, our findings open new avenues for implementing appropriate body composition assessments based on CT imaging.

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Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis

Horiuchi K., Ikemura S., Sato T., Shimozaki K., Okamori S., Yamada Y., Yokoyama Y., Hashimoto M., Jinzaki M., Hirai I., Funakoshi T., Mizuno R., Oya M., Hirata K., Hamamoto Y., Terai H., Yasuda H., Kawada I., Soejima K., Fukunaga K.

Oncologist 29 ( 1 ) E108 - E117 2024.01

ISSN 10837159

Background: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). Conclusion: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

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RECURRENT AND VIRTUAL EDUCATION FOR ALL DISCIPLINES AND OCCUPATIONS IN THE ALLERGY REALM：A SURVEY OF THE PARTICIPANTS FROM THE INITIATIVE 'OUTREACH LECTURES' TO CREATE EDUCATIONAL OPPORTUNITIES

Masaki K., Sakashita M., Ogawa Y., Inomata T., Kainuma K., Kan-O K., Sato S., Tamari M., Nakajima S., Morita H., Kurashima Y., Futamura M., Takahashi K., Haruta J., Hyakutake M., Monkawa T., Ishizuka T., Imoto Y., Oyama N., Kanzaki S., Kidoguchi M., Fukushima A., Fukunaga K., Fujieda S., Yasutomi M., Adachi T.

Japanese Journal of Allergology 73 ( 4 ) 329 - 339 2024

ISSN 00214884

Background: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate. Objective: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility. Methods: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list. Results: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied, ' and over 60% found the difficulty level 'appropriate. ' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience. Conclusion: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual/recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.

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THE INNATE IMMUNE NETWORK AND THERAPEUTIC APPROACHES IN ASTHMA

Baba R., Kabata H., Fukunaga K.

Japanese Journal of Allergology 73 ( 1 ) 14 - 20 2024

ISSN 00214884

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Estimating gene-level false discovery probability improves eQTL statistical fine-mapping precision

Wang Q.S., Edahiro R., Namkoong H., Hasegawa T., Shirai Y., Sonehara K., Kumanogoh A., Ishii M., Koike R., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K., Okada Y.

NAR Genomics and Bioinformatics 5 ( 4 ) 2023.12

Statistical fine-mapping prioritizes putative causal variants from a large number of candidate variants, and is widely used in expression quantitative loci (eQTLs) studies. In eQTL fine-mapping, the existence of causal variants for gene expression is not guaranteed, since the genetic heritability of gene expression explained by nearby (cis-) variants is limited. Here we introduce a refined fine-mapping algorithm, named Knockoff-Finemap combination (KFc). KFc estimates the probability that the causal variant(s) exist in the cis-window of a gene through construction of knockoff genotypes (i.e. a set of synthetic genotypes that resembles the original genotypes), and uses it to adjust the posterior inclusion probabilities (PIPs). Utilizing simulated gene expression data, we show that KFc results in calibrated PIP distribution with improved precision. When applied to gene expression data of 465 genotyped samples from the Japan COVID-19 Task Force (JCTF), KFc resulted in significant enrichment of a functional score as well as reporter assay hits in the top PIP bins. When combined with functional priors derived from an external fine-mapping study (GTEx), KFc resulted in a significantly higher proportion of hematopoietic trait putative causal variants in the top PIP bins. Our work presents improvements in the precision of a major fine-mapping algorithm.

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Time-dependent cell-state selection identifies transiently expressed genes regulating ILC2 activation

Tanaka Y., Yamagishi M., Motomura Y., Kamatani T., Oguchi Y., Suzuki N., Kiniwa T., Kabata H., Irie M., Tsunoda T., Miya F., Goda K., Ohara O., Funatsu T., Fukunaga K., Moro K., Uemura S., Shirasaki Y.

Communications Biology 6 ( 1 ) 2023.12

The decision of whether cells are activated or not is controlled through dynamic intracellular molecular networks. However, the low population of cells during the transition state of activation renders the analysis of the transcriptome of this state technically challenging. To address this issue, we have developed the Time-Dependent Cell-State Selection (TDCSS) technique, which employs live-cell imaging of secretion activity to detect an index of the transition state, followed by the simultaneous recovery of indexed cells for subsequent transcriptome analysis. In this study, we used the TDCSS technique to investigate the transition state of group 2 innate lymphoid cells (ILC2s) activation, which is indexed by the onset of interleukin (IL)-13 secretion. The TDCSS approach allowed us to identify time-dependent genes, including transiently induced genes (TIGs). Our findings of IL4 and MIR155HG as TIGs have shown a regulatory function in ILC2s activation.

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Cough and sputum in long COVID are associated with severe acute COVID-19: a Japanese cohort study

Watase M., Miyata J., Terai H., Sunata K., Matsuyama E., Asakura T., Namkoong H., Masaki K., Yagi K., Ohgino K., Chubachi S., Kawada I., Mochimaru T., Satomi R., Oyamada Y., Kobayashi K., Hirano T., Inoue T., Lee H., Sugihara K., Omori N., Sayama K., Mashimo S., Makino Y., Kaido T., Ishii M., Fukunaga K.

Respiratory Research 24 ( 1 ) 2023.12

ISSN 14659921

Background: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. Methods: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan–Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. Conclusions: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

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Clinical utilization of artificial intelligence-based COVID-19 pneumonia quantification using chest computed tomography – a multicenter retrospective cohort study in Japan

Tanaka H., Maetani T., Chubachi S., Tanabe N., Shiraishi Y., Asakura T., Namkoong H., Shimada T., Azekawa S., Otake S., Nakagawara K., Fukushima T., Watase M., Terai H., Sasaki M., Ueda S., Kato Y., Harada N., Suzuki S., Yoshida S., Tateno H., Yamada Y., Jinzaki M., Hirai T., Okada Y., Koike R., Ishii M., Hasegawa N., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Respiratory Research 24 ( 1 ) 2023.12

ISSN 14659921

Background: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions. Methods: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions. Results: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59–19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60–8.76), IMV requirement (aOR 7.73, 95% CI 2.52–23.7), and mortality rate (aOR 6.46, 95% CI 1.87–22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36–9.52), older age (aOR 2.53, 95% CI 1.16–5.51), female sex (aOR 2.41, 95% CI 1.13–5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09–4.50) independently predicted persistent residual lung lesions. Conclusions: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19.

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Clinical features of Japanese patients with gastrointestinal long-COVID symptoms

Yagi K., Asakura T., Terai H., Ohgino K., Masaki K., Namkoong H., Chubachi S., Miyata J., Kawada I., Kodama N., Sakamoto S., Umeda A., Ishiguro T., Ishii M., Fukunaga K.

JGH Open 7 ( 12 ) 998 - 1002 2023.12

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Characteristics of patients with COVID-19 who have deteriorating chest X-ray findings within 48 h: a retrospective cohort study

Kusumoto T., Chubachi S., Namkoong H., Tanaka H., Lee H., Otake S., Nakagawara K., Fukushima T., Morita A., Watase M., 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.

Scientific Reports 13 ( 1 ) 2023.12

The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). We investigated the clinical and genetic characteristics and prognosis of patients with worsening CXR findings during early hospitalization. We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases, high body temperature, and increased serum aspartate aminotransferase, potassium, and C-reactive protein levels were independent risk factors for rapid deterioration of CXR findings. Risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients. This study revealed the clinical features, genetic features, and risk factors associated with rapid deterioration of CXR findings, a poor prognostic factor in patients with COVID-19.

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Healthcare costs for hospitalized COVID-19 patients in a Japanese university hospital: a cross-sectional study

Uno S., Goto R., Honda K., Tokuda M., Kamata H., Chubachi S., Yamamoto R., Sato Y., Homma K., Uchida S., Namkoong H., Uwamino Y., Sasaki J., Fukunaga K., Hasegawa N.

Cost Effectiveness and Resource Allocation 21 ( 1 ) 2023.12

Background: A health-economic evaluation related to COVID-19 is urgently needed to allocate healthcare resources efficiently; however, relevant medical cost data in Japan concerning COVID-19 are scarce. Methods: This cross-sectional study investigated the healthcare cost for hospitalized COVID-19 patients in 2021 at Keio University Hospital. We calculated the healthcare costs during hospitalization using hospital claims data and investigated the variables significantly related to the healthcare cost with multivariable analysis. Results: The median healthcare cost per patient for the analyzed 330 patients was Japanese yen (JPY) 1,304,431 (US dollars ~ 11,871) (interquartile range: JPY 968,349–1,954,093), and the median length of stay was 10 days. The median healthcare cost was JPY 798,810 for mild cases; JPY 1,113,680 for moderate I cases; JPY 1,643,909 for moderate II cases; and JPY 6,210,607 for severe cases. Healthcare costs increased by 4.0% for each additional day of hospitalization; 1.26 times for moderate I cases, 1.64 times for moderate II cases, and 1.84 times for severe cases compared to mild cases; and 2.05 times for cases involving ICU stay compared to those not staying in ICU. Conclusions: We clarified the healthcare cost for hospitalized COVID-19 patients by severity in a Japanese university hospital. These costs contribute as inputs for forthcoming health economic evaluations for strategies for preventing and treating COVID-19.

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Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study

Suzuki S., Asakura K., Okui M., Izawa N., Sawafuji M., Sakamaki H., Shigenobu T., Tajima A., Oka N., Masai K., Kaseda K., Hishida T., Yasuda H., Fukunaga K., Asamura H.

World Journal of Surgical Oncology 21 ( 1 ) 2023.12

Background: The prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III–IV) NSCLC treated with salvage surgery after drug therapy. Methods: A retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications. Results: Thirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5–1024) ng/mL and 4.2 (range, 0.6–92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006–0.68] and 0.03 [0.002–0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%. Conclusions: In this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.

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Longitudinal significance of six-minute walk test in patients with nontuberculous mycobacterial pulmonary disease: an observational study

Morita A., Yagi K., Asakura T., Namkoong H., Sato Y., Ogawa T., Kusumoto T., Suzuki S., Tanaka H., Lee H., Okamori S., Azekawa S., Nakagawara K., Kaji M., Nagao G., Funatsu Y., Kimizuka Y., Kamata H., Nishimura T., Ishii M., Fukunaga K., Hasegawa N.

BMC Pulmonary Medicine 23 ( 1 ) 2023.12

Background: The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. Methods: Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George’s Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. Results: The median age [interquartile range] of the patients was 67 [63–74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361–470] m and 1 [0–2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. Conclusions: The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient’s condition and tailor their healthcare environment.

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Longitudinal long COVID symptoms in Japanese patients after COVID-19 vaccinations

Nakagawara K., Morita A., Namkoong H., Terai H., Chubachi S., Asakura T., Tanaka H., Ito F., Matsuyama E., Kaji M., Saito A., Takaoka H., Okada M., Sunata K., Watase M., Yagi K., Ohgino K., Miyata J., Kamata H., Kawada I., Kobayashi K., Hirano T., Inoue T., Kagyo J., Shiomi T., Otsuka K., Miyao N., Odani T., Baba R., Arai D., Nakachi I., Ueda S., Funatsu Y., Koh H., Ishioka K., Takahashi S., Nakamura M., Sato T., Hasegawa N., Kitagawa Y., Kanai T., Ishii M., Fukunaga K.

Vaccine: X 15 2023.12

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

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Interaction of BMI and respiratory status in obstructive sleep apnea, a cross-sectional COPD study

Hashiguchi M.H., Chubachi S., Yamasawa W., Otsuka K., Harada N., Miyao N., Nakamura H., Asano K., Yamaguchi K., Fukunaga K.

npj Primary Care Respiratory Medicine 33 ( 1 ) 2023.12

This cross-sectional study of 136 patients with chronic obstructive pulmonary disease (COPD) investigated the mechanism underlying overlap syndrome, defined as coexisting COPD and obstructive sleep apnea (OSA). OSA was defined as a respiratory event index (REI) ≥ 5 events/h, determined using type-3 portable monitors. The mean REI was 12.8 events/h. Most participants (60.1%) had mild OSA (REI: 5–15 events/h). The REI was positively correlated with forced expiratory volume in one second (%FEV1) (r = 0.33, p < 0.001), body mass index (BMI) (r = 0.24, p = 0.005), and fat-free mass index (r = 0.31, p = 0.005), and negatively correlated with residual volume divided by total lung capacity (r = −0.27, p = 0.003). Receiver-operating characteristic curve analysis revealed an optimal BMI cutoff of 21.96 kg/m2 for predicting moderate/severe OSA. A BMI ≥ 21.96 kg/m2 was associated with OSA among participants with %FEV1 ≥ 50%, but not those with %FEV1 < 50%. This study revealed an interaction between airflow limitation and hyperinflation, nutritional status, and OSA.

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Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study

Nakagawara K., Kamata H., Chubachi S., Namkoong H., Tanaka H., Lee H., Otake S., Fukushima T., Kusumoto T., Morita A., Azekawa S., Watase M., Asakura T., Masaki K., Ishii M., Endo A., Koike R., Ishikura H., Takata T., Matsushita Y., Harada N., Kokutou H., Yoshiyama T., Kataoka K., Mutoh Y., Miyawaki M., Ueda S., Ono H., Ono T., Shoko T., Muranaka H., Kawamura K., Mori N., Mochimaru T., Fukui M., Chihara Y., Nagasaki Y., Okamoto M., Amishima M., Odani T., Tani M., Nishi K., Shirai Y., Edahiro R., Ando A., Hashimoto N., Ogura S., Kitagawa Y., Kita T., Kagaya T., Kimura Y., Miyazawa N., Tsuchida T., Fujitani S., Murakami K., Sano H., Sato Y., Tanino Y., Otsuki R., Mashimo S., Kuramochi M., Hosoda Y., Hasegawa Y., Ueda T., Takaku Y., Ishiguro T., Fujiwara A., Kuwahara N., Kitamura H., Hagiwara E., Nakamori Y., Saito F., Kono Y., Abe S., Ishii T., Ohba T., Kusaka Y., Watanabe H., Masuda M., Watanabe H., Kimizuka Y., Kawana A., Kasamatsu Y., Hashimoto S., Okada Y., Takano T., Katayama K., Ai M., Kumanogoh A., Sato T., Tokunaga K., Imoto S., Kitagawa Y., Kimura A., Miyano S., Hasegawa N., Ogawa S., Kanai T., Fukunaga K.

BMC Pulmonary Medicine 23 ( 1 ) 2023.12

Background: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. Methods: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. Results: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil–lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. Conclusions: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

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Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma—Factor analysis

Okada N., Yamamoto Y., Oguma T., Tanaka J., Tomomatsu K., Shiraishi Y., Matsuse H., Shimoda T., Kimura H., Watai K., Harada T., Fujita Y., Obase Y., Suzukawa M., Suzuki J., Takayanagi N., Ishiguro T., Masaki K., Fukunaga K., Asano K.

Allergy: European Journal of Allergy and Clinical Immunology 78 ( 11 ) 2933 - 2943 2023.11

ISSN 01054538

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. Methods: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. Results: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p <.001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. Conclusion: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

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