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.

Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis. A Report of Five Intractable Cases.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema.

BACKGROUND AND OBJECTIVE: The molecular mechanisms underlying COPD remain undetermined. The lungs of surfactant protein-D (SP-D) deficient mice show emphysema and an excessive number of foamy macrophages. This study aims to elucidate roles of SP-D and foamy macrophages in smoking-induced mouse emphysema. METHODS: Twenty B6C3F1 mice were exposed to cigarette smoke (2 cigarettes/day/mouse for 6 months). The mice were killed, and formalin-fixed, paraffin-embedded lung sections were carried out on seven mice, BAL was carried out on six mice, and seven mice were used to make lung homogenates. In in vitro studies, A549 cells were transduced with the SP-D expression plasmid and treated with cigarette smoke extract to evaluate cell viability. RESULTS: Emphysema was induced in the mice by chronic cigarette smoke exposure. Increased expression of matrix metalloproteinase-9 and -12 was observed, and foamy alveolar macrophages accumulated in the smoke-exposed lungs. Immunostaining of BAL cells revealed the major source of matrix metalloproteinase-12 to be foamy alveolar macrophages. Furthermore, SP-D was elevated in emphysema lungs. Expression of transcription factors, Fra-1, junB and C/EBPbeta (which induce SP-D) were significantly elevated in emphysema lungs. The in vitro expression of SP-D gene in A549 cells prolonged cell survival following exposure to cigarette smoke condensate. CONCLUSIONS: The accumulation of foamy alveolar macrophages may play a key role in the development of smoking-induced emphysema. Increased SP-D may play a protective role in the development of smoking-induced emphysema, in part by preventing alveolar cell death.

Intronic single-nucleotide polymorphisms in Bcl-2 are associated with chronic obstructive pulmonary disease severity.

BACKGROUND AND OBJECTIVE: COPD is a multifactorial disease influenced by genetic and environmental factors, and gene-by-environmental interactions. There is considerable variability in the degree of airflow obstruction, moreover only 10-15% of chronic smokers develop COPD. These observations indicate that additional risk factors, possibly genetic, contribute to not only the susceptibility to COPD but also the development and severity of COPD. Recent paradigms highlight the presence and causal role of apoptosis in emphysema. There is a large amount of information on the genes involved in the regulation of apoptosis and one of the most studied is Bcl-2. The aim of this study was to investigate the genetic association of Bcl-2 gene with the level of lung function, that is, the severity, of COPD. METHODS: The genetic association of Bcl-2 polymorphisms with lung function was investigated in 261 Japanese patients with COPD using 12 single-nucleotide polymorphisms (SNPs) in Bcl-2. RESULTS: Four SNPs showed a significant association between the high and low lung function groups in a dominant trait comparison. Subsequent linkage-disequilibrium mapping and analyses of haplotype structure also showed a significant association between the level of lung function and two haplotypes comprised of the associated SNPs in Bcl-2. CONCLUSIONS: Although the linkage between Bcl-2 gene and the susceptibility to COPD remains to be clarified, the findings of the current study indicate that Bcl-2 might be influencing the level of lung function, that is, the development and severity of COPD.

Clarithromycin suppresses invasiveness of human lung adenocarcinoma cells.

BACKGROUND: It has been speculated that clarithromycin (CAM), a 14-membered ring macrolide, possesses antitumor effects besides antimicrobial and anti-inflammatory effects. METHOD: We evaluated the effects of CAM on the growth and invasiveness of A549 lung adenocarcinoma cells. RESULTS: Although CAM did not affect the growth of A549 cells, the Matrigel invasion assay showed that the potential of invasion was diminished by CAM treatment. When analyzed by flow cytometry, CAM suppressed alpha(2)- and beta(1)-integrin expression. Furthermore, thymidine phosphorylase (TP) expression was diminished by CAM treatment in a dose-dependent manner. A specific TP inhibitor also suppressed beta(1)-integrin expression in flow cytometric analysis. CONCLUSIONS: These results suggest that CAM may suppress invasive activity of A549 cells in part by diminishing the expression of TP, alpha(2)- and beta(1)-integrin, which may be a downstream signal of the TP pathway, and that CAM could be useful in the treatment of lung adenocarcinoma.

Enhanced expression of MafB inhibits macrophage apoptosis induced by cigarette smoke exposure.

In the lungs of smokers, oxidative stress rises due to increase of free radicals and oxidants, including lipid peroxide (LPO). The functions of alveolar macrophages (AMs) are altered in such an environment, and their survival is prolonged against toxicities of cigarette smoke (CS) by an unknown mechanism. Whereas functions of AMs are potentially regulated by various transcriptional factors, their expressions and roles in smoking individuals have not been elucidated. Therefore, we investigated their expressions using murine model of CS exposure. Eight-week-old male B6C3F1 mice were whole-bodily exposed to CS (2 cigarettes/mouse/day, 5 d/wk) for 6 mo. Development of pulmonary emphysema in 6-mo CS-exposed mice was confirmed by a morphometric analysis. Among the transcriptional factors investigated, only MafB was upregulated in AMs from CS-exposed mice. DNA binding capacity of MafB for Maf recognition element was also increased in AMs from those mice. LPO was increased significantly in the lungs of CS-exposed mice. Because the end product of LPO, 4-hydroxy-2-nonenal, enhanced MafB expression and its transcriptional activity in a cultured macrophage cell line, LPO-related oxidative stress was suggested to be involved in the mechanism of MafB expression in CS-exposed lung. Furthermore, we established a macrophage cell line that can overexpress MafB and thereby clarify the role of MafB. Forced expression of MafB heightened cell viability and attenuated the occurrence of apoptosis in cells treated with CS-extract. These results suggest that enhanced MafB expression by oxidative stress inhibits AM cell death and prolongs their survival in the CS-exposed lung.

A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease.

RATIONALE: Acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality in COPD. OBJECTIVES: The marked heterogeneity in the host defense mechanisms may be attributed to single nucleotide polymorphisms (SNPs) in the inflammatory chemokines that show enhanced expression in the airway of patients with COPD who experience AEs. METHODS: We investigated four SNPs of the CCL11, CCL1, and CCL5 genes in relation to the frequency and severity of AEs in retrospective and prospective studies of a cohort of 276 male patients with COPD. MEASUREMENTS AND MAIN RESULTS: In the 2-yr retrospective study , one SNP (National Center for Biotechnology Information SNP reference: rs2282691) in the predicted enhancer region of the CCL1 gene, encoding a chemotactic factor for a series of leukocytes, was significantly associated with the frequency of AEs in a dominant model (Fisher's exact test: odds ratio [OR], 2.70; 95% confidence interval [CI], 1.36-5.36; p=0.004; logistic regression: OR, 3.06; 95% CI, 1.46-6.41; p=0.003; and Kruskal-Wallis test: p=0.003). In the 30-mo prospective study, the "A" allele was a significant risk allele for the severity of AEs, with a gene-dosage effect (Kaplan-Meier method with log-rank test: AA vs. TT; log-rank statistic: 7.67, p=0.006; Cox proportional hazards regression method: OR, 5.93; 95% CI, 1.28-27.48; p=0.023). The electromobility shift assay showed that C/EBPbeta, a key transcriptional factor in response to pulmonary infections, binds to the "T" allele, but not to the "A" allele. CONCLUSIONS: Variants in the CCL1 gene are associated with susceptibility to AEs through their potential implication in the host defense mechanisms against AEs.

A novel polymorphism in secretory phospholipase A2-IID is associated with body weight loss in chronic obstructive pulmonary disease.

RATIONALE: Chronic and systemic inflammation, a potential cause of body weight loss in patients with chronic obstructive pulmonary disease (COPD), may be associated with the proinflammatory properties of secretory phospholipases A2 (sPLA2s), especially the group II subfamily sPLA2s. OBJECTIVES: We tested our hypothesis that the individual susceptibility to body weight loss in patients with COPD is attributed to the genetic variances of this sPLA2 gene region. METHODS: A total of 12 single nucleotide polymorphisms (SNPs) encompassing the sPLA2 gene region were determined in 276 male patients with COPD. MEASUREMENTS AND MAIN RESULTS: We first analyzed our patients whose body mass index (BMI) was at the bottom 100 (BMI, 17.13 +/- 1.29 kg/m2) and at the top 100 (23.83 +/- 1.98) in relation to SNPs. Both the Fisher's exact test (odds ratio, 2.36; 95% confidence interval, 1.34-4.18; p = 0.004) and logistic regression analysis (odds ratio, 2.10; 95% confidence interval, 1.13-3.90; p = 0.019) showed statistical significance between one SNP (National Center for Biotechnology Information SNP reference: rs584367) and the reduction of BMI in the recessive model in patients with COPD. Using all the patients, a significant difference between the values of BMI (log transformed) of the mutant group (CT + TT) and that of the nonmutant group (CC) of this SNP (mean [SE], 1.293 [0.005] vs. 1.317 [0.006]; p = 0.003) was found after adjustment for age, smoking habit, and pulmonary function (analysis of covariance). Importantly, this SNP caused a change in amino acids in sPLA2-IID protein (Gly80Ser). CONCLUSIONS: These results suggest that sPLA2-IID may be one of the susceptibility genes that contribute to body weight loss in patients with COPD.

Antineutrophil cytoplasmic antibody positive alveolar haemorrhage during propylthiouracil therapy for hyperthyroidism.

Recently, propylthiouracil (PTU) has been thought to be one of the possible causes of antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis syndrome, resulting in glomerulonephritis and, infrequently, diffuse alveolar haemorrhage (DAH). The mechanism of ANCA-positive vasculitis during PTU therapy is still unknown. Herein, we describe the case of a 59-year-old woman who developed myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA positive DAH, without any other organ system involvement, during PTU therapy. Diminution and discontinuation of PTU resulted in a positive response. To our knowledge, this is the first documentation of both MPO- and PR3-ANCA-positive DAH, without systemic manifestations, developing during PTU therapy.