Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic.

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

A phase II trial of erlotinib monotherapy for pretreated elderly patients with advanced EGFR wild-type non-small cell lung cancer.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is an effective treatment for patients with non-small cell lung cancer (NSCLC), especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second- or third-line erlotinib monotherapy for elderly patients with EGFR-wt advanced or recurrent NSCLC. METHODS: Pretreated patients aged ≥70 years with EGFR-wt stage IIIB/IV NSCLC or those with postoperative recurrence were enrolled and received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range 70-84 years). Six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0. Eleven (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% [95% confidence interval (CI) 0-17.1]. DCR was 56.3% (95% CI 33.2-76.9). The median PFS and OS were 1.7 months (95% CI 1.3-2.2) and 7.2 months (95% CI 5.6-8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which improved following steroid therapy. CONCLUSIONS: In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second line therapy. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004561 (Date of registration: November 15th, 2010).

Clinical significance of serum hyaluronan in chronic fibrotic interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Hyaluronan is an important constituent of the extracellular matrix in lungs, and growing evidence demonstrates its important biological properties in the lung. However, its role in interstitial pneumonia remains to be fully clarified. The goal of this study was to clarify the role of hyaluronan in interstitial pneumonia. METHODS: Hyaluronan in serum and bronchoalveolar lavage (BAL) fluid of chronic interstitial pneumonia (CIP) patients was measured, and the correlation with clinical parameters was determined. In addition, the correlation between hyaluronan in serum and clinical parameters was analysed in patients with acute exacerbation of interstitial pneumonia (IP-AE). RESULTS: When compared with healthy controls, serum hyaluronan was significantly greater in patients with CIP and was positively correlated with serum biomarkers of inflammation and fibrosis, such as C-reactive protein and surfactant protein-D. In BAL fluid, the amount of hyaluronan was positively correlated with the percentage of inflammatory cells and the amount of CXCL8. When compared with CIP patients, patients with IP-AE had significantly greater amounts of serum hyaluronan, and patients with the highest serum hyaluronan had the worst 60-day outcomes. CONCLUSIONS: This work suggests that serum hyaluronan may be a clinically useful biomarker of interstitial pneumonia and suggests the possibility that hyaluronan is involved in the pathogenesis of interstitial pneumonia by recruiting inflammatory cells into the lungs.

Association of asthma education with asthma control evaluated by asthma control test, FEV1, and fractional exhaled nitric oxide.

BACKGROUND: Asthma education is an important adjunct for asthma control although the way asthma education affects asthma outcomes is poorly understood. The asthma control test (ACT), forced expiratory volume in 1 s (FEV(1)), and fractional exhaled nitric oxide (FeNO) have all been used as markers of asthma control. However, the use of FeNO as a surrogate marker remains controversial. OBJECTIVES: (i) To examine whether asthma education is associated with asthma control; (ii) to compare absolute levels and changes of ACT, FEV(1), and FeNO over a year; and (iii) to evaluate whether FeNO can be used as an additional marker of asthma control. METHODS: Fifty asthmatics with poor adherence (12 mild, 21 moderate, and 17 severe) received asthma education at study entry. Medications were unchanged for the first 3 months, and ACT, FEV(1), and FeNO measurements were recorded at entry, 3, 6, and 12 months. Asthma control was assessed at each visit and patients were categorized as either "stable" or "unstable" asthmatics according to the global initiative for asthma (GINA) guidelines. RESULTS: A significant decrease in FeNO and increase in ACT score were noted in the stable asthmatic group at 3 months (p < .001), and this persisted over 12 months. Significant correlations were seen between changes (Δ) in FeNO, ACT, and FEV(1) over time. However, significant correlations between the absolute levels were not maintained over 12 months. A decrease of ≥18.6% in FeNO and a ≥3-point increase in ACT score (sensitivity: 80% and 73.3% and specificity: 83.3% and 87.5%, respectively) were associated with stable asthma control although the absolute levels were not. CONCLUSIONS: Asthma education may be useful to achieve stable control. In addition, changes rather than absolute levels of FeNO and ACT may be better markers of asthma control.

Relationship between 25-hydroxyvitamin D levels and treatment course of pulmonary tuberculosis.

BACKGROUND: Low serum vitamin D level is associated with a high risk of developing active tuberculosis (TB). We investigated the relationships between serum vitamin D levels and clinical course of TB after standard chemotherapy in hospitalized non-HIV patients with TB. METHODS: Hospitalized patients with TB were recruited between February 2008 and July 2010. Confirmatory tests were performed using sputum smear and culture positivity tests for Mycobacterium tuberculosis. Drug sensitivity testing was performed for all the subjects and those not showing drug resistances for the first-line anti-TB drugs were included in the study. These patients were treated with the standard first-line anti-TB drugs. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured on admission, and the relationships between 25(OH)D and clinical characteristics (laboratory data on admission and treatment outcomes) were examined. We defined vitamin D deficiency as a condition where serum level of 25(OH)D was lower than 20 ng/ml. RESULTS: A total of 38 patients were included in the study. Mean (± SD) 25(OH)D levels were 13.7 ± 5.9 ng/ml. The prevalence of vitamin D deficiency was 87%. In 23 patients treated with the standard first-line 4-drug regimen (Age < 80 years) serum 25(OH)D levels showed significant negative correlation with time taken to obtain 3 consecutive negative sputum smears or TB bacteria cultures. This relationship suggests that low serum vitamin D level may not only increase the risk of developing active TB but may also be related to the poor treatment outcomes in these patients. CONCLUSIONS: Low serum vitamin D level is a good predictor of prolonged clinical course in patients with active pulmonary TB.

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. METHODS: Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. RESULTS: Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb-IV). CONCLUSIONS: While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Validation study of asthma screening criteria based on subjective symptoms and fractional exhaled nitric oxide.

BACKGROUND: In the latest Global Initiative for Asthma guideline, neither sputum eosinophilia nor fractional exhaled nitric oxide (FeNO) have been evaluated prospectively as an aid in asthma diagnosis, but these measurements are being evaluated for potential use in determining optimal treatment. OBJECTIVE: To report criteria for screening asthma using subjective symptoms and FeNO levels and results of a prospective validation study using these criteria. METHODS: Sixty-one outpatients with recurrent cough, wheezing, or dyspnea underwent measurements of FeNO levels, pulmonary function, methacholine airway responsiveness, and inflammatory cells in induced sputum. The sensitivity, specificity, and concordance achieved using the FeNO-based criteria (at least 1 of the following subjective symptoms: recurrent cough, wheezing, or dyspnea and/or FeNO level ≥ 40 ppb) were analyzed and compared with the values obtained using conventional asthma diagnostic criteria, which includes subjective symptoms with any 2 of the following conditions: airway hyperresponsiveness, reversible airflow limitation, and eosinophilia in induced sputum. RESULTS: Of the 61 patients, 41 were diagnosed as having asthma by the conventional criteria, and 33 were diagnosed as having asthma by the FeNO-based criteria, which showed a sensitivity of 78.6%, a specificity of 89.5%, and a concordance rate of 0.62. Nine of 42 patients were misdiagnosed as not having asthma by FeNO-based criteria (mean [SD] FeNO level, 23.9 [8.0] ppb). Seven of 9 patients were diagnosed as having nonatopic asthma according to IgE levels. CONCLUSIONS: Asthma may be accurately diagnosed in daily practice on the basis of subjective symptoms and FeNO levels, particularly in atopic patients.

[Differences of fractional exhaled nitric oxide (FeNO) levels performed using two different analyzers].

The measurement of fractional exhaled nitric oxide (FeNO) is going to become more wide-spread as a noninvasive marker for diagnosing and controlling bronchial asthma. In Japan, both stationary and portable FeNO analyzers are now available. However, the difference between these analyzers has not been fully examined. Therefore, the aim of this study is to determine whether there is a difference between a stationary FeNO analyzer (NA623NP, CHEST inc. Tokyo, Japan) and a portable analyzer (NIOX MINO, Aerocrine, Solna, Sweden). One hundred subjects (17 non-treated asthma cases, 45 asthma cases treated with inhaled corticosteroids, 21 with other respiratory disorders, 17 healthy subjects) were enrolled in the study. All the subjects were non- or ex-smokers. There was a strong positive correlation between FeNO (CHEST) and FeNO (MINO) (r = 0.970, p < 0.001). However, when FeNO levels between FeNO (CHEST) and FeNO (MINO) were compared in all subjects and each subject group, the levels of FeNO (MINO) were significantly lower than those of FeNO (CHEST) (p < 0.05). Finally, the following conversion equation was calculated: FeNO (CHEST) = FeNO (MINO) x 1.278 + 3.065. From these results, the following conclusion was drawn: when FeNO is measured by different analyzers, there might be differences between devices. Therefore, the conversion equation could help clinicians and researchers to compare data obtainable by these two analyzers.

[Transesophageal endoscopic ultrasonography guided-fine needle aspiration for the diagnosis of sarcoidosis].

Sarcoidosis is a multi-organ disorder of unknown etiology characterized by noncaseating epithelioid cell granulomas. The specimen for histopathological diagnosis is usually obtained by transbronchial lung biopsy (TBLB), but the diagnostic accuracy rate of TBLB is not satisfactory, especially for stage I patients. Since hilar and mediastinal lymphadenopathy is a common finding in patients with sarcoidosis, an approach to lymph nodes is expected to have a good diagnosis yield. We present 3 sarcoidosis patients in whom specimens obtained by TBLB, transbronchial needle aspiration (TBNA) and transesophageal endoscopic ultrasonography guided-fine needle aspiration (EUS-FNA). The histopathological appearance of specimens obtained by EUS-FNA for swollen mediastinal lymph nodes showed noncaseating epithelioid granulomas which are characteristic of sarcoidosis in all 3 patients. On the other hand, no specific findings were recognized in the specimens obtained by TBLB and TBNA in 2 out of 3 patients. These results suggest that EUS-FNA is useful to obtain diagnostic specimens in cases of sarcoidosis.

[Solitary pulmonary nodule due to Mycobacterium intracellulare showing intense uptake on 18F-fluorodeoxyglucose-positron emission tomography].

A 71-year-old woman with no respiratory symptoms, was admitted because of a solitary pulmonary nodule on a chest radiograph. Computed tomography revealed a 2.0 cm nodule with pleural indentation in the right S2. 18F-fluorodeoxyglucose-positron emission (18F-FDG-PET) showed positive tumor uptake (maximum standardized uptake value = 4.8). Bronchoscopy yielded no specific histological or bacterial findings. Lung biopsy using video-associated thoracoscopy revealed an epithelial granuloma with caseation, but no acid-fast bacilli were detected. PCR revealed Mycobacterium intracellulare (M. intracellulare). A solitary nodule caused by M. intracellulare is rare, but it should be considered in the differential diagnosis even with intense uptake on 18F-FDG-PET.