Diagnostic significance of secondary bacteremia in patients with COVID-19.

OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

An observational cohort study of interstitial lung abnormalities (ILAs) in a large Japanese health screening population (Kumamoto ILA study in Japan: KILA-J).

BACKGROUND: Interstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment. METHODS: This is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence. DISCUSSION: This is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases. TRIAL REGISTRATION NUMBER: UMIN000045149.

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

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.

Health Care Resource Use Among Patients with Advanced Non-Small Cell Lung Cancer in Japan, 2017-2019.

Background: First-line immune checkpoint inhibitor (ICI) monotherapy for advanced non-small cell lung cancer (NSCLC) was introduced in Japan in February 2017. Limited information is available since that time regarding health care resource use for NSCLC in Japan, where the hospitalization burden is high. Objective: We evaluated health care resource use from first- through third-line systemic anticancer therapy for patients with advanced NSCLC included in a multicenter, retrospective chart review study. Methods: Eligible patients were aged 20 years or older with unresectable locally advanced/metastatic NSCLC with no known actionable genomic alteration who initiated first-line systemic anticancer therapy from July 1, 2017, to December 20, 2018, at 23 Japanese hospitals. We calculated the percentage of patients with a record of each resource used, the total number of each resource, and the resource use per 100 patient-weeks of follow-up from initiation of first-, second-, and third-line therapy, overall and by the 3 most common regimen categories, namely, ICI monotherapy, platinum-doublet chemotherapy (without concomitant ICI), and nonplatinum cytotoxic regimens (nonplatinum). Study follow-up ended September 30, 2019. Results: Among 1208 patients (median age = 70 years; 975 [81%] men), 463 patients (38%) received ICI monotherapy, 647 (54%) received platinum-doublet chemotherapy, and 98 (8%) received nonplatinum regimens as first-line therapy. During the study, 621 (51%) patients initiated second-line, and 281 (23%) initiated third-line therapy. The majority of patients experienced ≥1 hospitalization (76%-94%) and ≥1 outpatient visit (85%-90%) during each therapy line. The number of hospitalizations increased from 6.5 per 100 patient-weeks in first-line to 8.0 per 100 patient-weeks in third-line. During first-line therapy, the number of hospitalizations per 100 patient-weeks were 4.8, 8.4, and 6.5 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of hospitalizations categorized as attributable to NSCLC treatment administration (no surgery, procedure, treatment of metastasis, or palliative lung radiation) were 64%, 77%, and 73%, respectively. The number of outpatient visits increased from 43.0 per 100 patient-weeks in first-line to 51.4 per 100 patient-weeks in third-line therapy. During first-line therapy, outpatient visits per 100 patient-weeks were 41.0, 46.7, and 33.0 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of outpatient visits for infusion therapy were 48%, 34%, and 36%, respectively. Conclusions: The results of this study, although solely descriptive, showed differing patterns of health care resource use during first-line therapy among the 3 common systemic anticancer therapy regimens for advanced NSCLC in Japan and suggest that further research is needed to investigate these apparent differences by treatment regimen.

A Randomized Phase 2 Study of 5-Aminolevulinic Acid Hydrochloride and Sodium Ferrous Citrate for the Prevention of Nephrotoxicity Induced by Cisplatin-Based Chemotherapy of Lung Cancer.

INTRODUCTION: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. METHODS: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. RESULTS: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m2, respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m2, respectively, p = 0.013). CONCLUSIONS: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.

Early corticosteroid dose tapering in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively). CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Monocyte count and the risk for acute exacerbation of fibrosing interstitial lung disease: A retrospective cohort study.

Recent studies have suggested that an increased peripheral monocyte count predicts a poor outcome in fibrosing interstitial lung disease (ILD). However, the association between an increased monocyte count and acute exacerbations (AEs) of fibrosing ILD remains to be elucidated. Our retrospective cohort study aimed to assess the impact of peripheral monocyte count on AEs of fibrosing ILD. We analyzed the electronic medical records of 122 consecutive patients with fibrosing ILD and no prior history of an AE, who were treated with anti-fibrotic agents from August 2015 to December 2018. We determined their peripheral monocyte counts at anti-fibrotic agent initiation and performed univariate and multivariate Cox regression analyses of time-to-first AE after anti-fibrotic agent initiation to assess the impact of monocyte count on AEs of fibrosing ILD. Twenty-six patients developed an AE during the follow-up period, and there was an increased monocyte count at anti-fibrotic agent initiation in these patients compared to those who did not develop an AE. There was also a significantly shorter time-to-first AE of fibrosing ILD in patients with a higher absolute monocyte count. Subgroup analyses indicated similar results regardless of the idiopathic pulmonary fibrosis diagnoses. This association was independently significant after adjusting for the severity of the fibrosing ILD. Using our results, we developed a simple scoring system consisting of two factors-monocyte count (<>380 µL-1) and ILD-gender, age, physiology score (<>4 points). Our findings suggest that the absolute monocyte count is an independent significant risk factor for AE in patients with fibrosing ILD. Our simple scoring system may be a predictor for AEs of fibrosing ILD, although further studies are needed to verify our findings.

Acute exacerbation of chronic fibrosing interstitial pneumonia in patients receiving antifibrotic agents: incidence and risk factors from real-world experience.

BACKGROUND AND OBJECTIVE: Here, we present real-world data on the incidence and risk factors of acute exacerbation (AE) in patients with chronic fibrotic interstitial pneumonia (CFIP) treated with antifibrotic agents, which has been previously poorly documented. METHODS: We retrospectively examined clinical characteristics, incidence and risk factors of AE in a cohort of 100 patients with CFIP (n = 75, idiopathic pulmonary fibrosis [IPF]; n = 25, other conditions), all of whom received antifibrotic agents in a real-world setting. RESULTS: The median follow-up was 17.4 months (interquartile range [IQR], 6.6 to 26.7 months). During the follow-up periods, 21 patients experienced AE after starting antifibrotic agents. The estimated 1-, 2-, and 3-year AE incidence rates were 11.4% (95% confidence interval [95%CI], 6.2-20.3%), 32% (95%CI, 20.7-47.4%), and 36.3% (95%CI 23.5-53.1%), respectively. Decreased baseline lung function (forced vital capacity and carbon monoxide diffusing capacity of the lung), existence of pulmonary hypertension estimated from an echocardiogram, higher Interstitial Lung Disease-Gender, Age, and Physiology (ILD-GAP) score, supplementary oxygen, and concomitant corticosteroid and proton-pump inhibitor (PPI) use upon starting the antifibrotic agent were risk factors of AE. Concomitant corticosteroid and PPI use and corticosteroid dose were risk factor of AE in a multivariate Cox regression hazard model adjusting for ILD-GAP score. CONCLUSION: AE of CFIP is more common in patients with physiologically and functionally advanced disease under antifibrotic agents. Prudent use of corticosteroids and PPIs when initiating antifibrotic agents may be recommended. Further studies are warranted.

The negative effect of initial high-dose methylprednisolone and tapering regimen for acute respiratory distress syndrome: a retrospective propensity matched cohort study.

BACKGROUND: The efficacy of corticosteroid use in acute respiratory distress syndrome (ARDS) remains controversial. Generally, short-term high-dose corticosteroid therapy is considered to be ineffective in ARDS. On the other hand, low-dose, long-term use of corticosteroids has been reported to be effective since they provide continued inhibition of the systemic inflammatory response syndrome (SIRS) that accompanies ARDS. Thus far, no reports have been published on the efficacy of initiating treatment with a high-dose corticosteroid regimen with tapering. METHODS: We conducted a retrospective observational study involving 186 patients treated at a teaching hospital (68% had sepsis, pneumonia, or aspiration pneumonia). ARDS was diagnosed according to the Berlin definition. Patients were divided into a high-dose (n = 21) or low-dose corticosteroid group (n = 165) to compare the effectiveness of a down-titration regimen. The primary medical team chose which treatment a patient would receive. We were careful to conduct a differential diagnosis of interstitial pneumonia (e.g., acute eosinophilic pneumonia) since corticosteroid treatment has been proven effective in that patient population. The primary outcome was the 60-day mortality rate. The secondary outcome was the number of ventilator-free days (VFD). RESULTS: Those started on a high-dose regimen had a significantly higher 60-day mortality rate (P = 0.031) with significantly fewer VFD (P = 0.021). Propensity scores were used to adjust patient backgrounds in a variable analysis that also showed the high-dose regimen was a factor in decreasing VFD (OR, 95.63; 95% CI, 1.74-5271.07; P = 0.026) and worsening the 60-day mortality rate (OR, 2.54; 95% CI, 0.92-7.02; P = 0.072). CONCLUSIONS: A tapering regimen after high-dose corticosteroids is likely to increase ventilator dependency and might aggravate the prognosis of patients with ARDS diagnosed according to the Berlin definition.

Case report: continued treatment with alectinib is possible for patients with lung adenocarcinoma with drug-induced interstitial lung disease.

BACKGROUND: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is a key drug for ALK rearranged lung adenocarcinoma. Interstitial lung disease (ILD) is an important adverse effect of alectinib, which generally requires termination of treatment. However, we treated two patients with drug-induced ILD who continued to receive alectinib. CASE PRESENTATION: Patient 1 was a 57-year-old male with an ALK-rearranged Stage IV lung adenocarcinoma who was administered alectinib as first-line therapy. Computed tomography (CT) detected asymptomatic ground-glass opacity (GGO) on day 33 of treatment. Alectinib therapy was therefore discontinued for 7 days and then restarted. GGO disappeared, and the progression of ILD ceased. Patient 2 was a 64-year-old woman with an ALK-positive lung adenocarcinoma who was administered alectinib as third-line therapy. One year later, CT detected GGO; and she had a slight, nonproductive cough. Alectinib therapy was continued in the absence of other symptoms, and GGO slightly diminished after 7 days. Two months later, CT detected increased GGO, and alectinib therapy was continued. GGO diminished again after 7 days. The patient has taken alectinib for more than 2 years without progression of ILD. CONCLUSIONS: Certain patients with alectinib-induced ILD Grade 2 or less may continue alectinib therapy if they are closely managed.

Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition without an established pharmaceutical treatment. Most patients are treated with high-dose corticosteroids and broad-spectrum antibiotics. Azithromycin is a macrolide with immunomodulatory activity and may be beneficial for treatment of acute lung injury. The objective of this study was to determine the effect of azithromycin on survival of patients with idiopathic AE of IPF. METHODS: We evaluated 85 consecutive patients hospitalized in our department for idiopathic AE of IPF from April 2005 to August 2016. The initial 47 patients were treated with a fluoroquinolone-based regimen (control group), and the following 38 consecutive patients were treated with azithromycin (500 mg/day) for 5 days. Idiopathic AE of IPF was defined using the criteria established by the 2016 International Working Group. RESULTS: Mortality in patients treated with azithromycin was significantly lower than in those treated with fluoroquinolones (azithromycin, 26% vs. control, 70%; p < 0.001). Multivariate analysis revealed that the two variables were independently correlated with 60-day mortality as determined by the Acute Physiology and Chronic Health Evaluation II score (p = 0.002) and azithromycin use (p < 0.001). CONCLUSION: Azithromycin may improve survival in patients with idiopathic AE of IPF.

Efficacy of azithromycin for treatment of acute exacerbation of chronic fibrosing interstitial pneumonia: a prospective, open-label study with historical controls.

BACKGROUND: Acute exacerbation of chronic fibrosing interstitial pneumonia (AE-CFIP) is an often fatal condition with no established treatment. Recently, macrolides were found to be beneficial in cases of acute lung injury. OBJECTIVES: To examine the clinical effectiveness and safety of intravenous azithromycin in patients hospitalized for AE-CFIP. METHODS: A prospective, open-label study with historical controls was conducted. Twenty consecutive patients with AE-CFIP received azithromycin. They were compared with a historical cohort treated with fluoroquinolone (n = 56). All patients received high-dose steroid pulse therapy. The primary end point was mortality at 60 days. The secondary end point was safety of intravenous azithromycin in patients with AE-CFIP. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to investigate the relationship between azithromycin use and survival time. RESULTS: Mortality was significantly lower in the patients treated with azithromycin than in those treated with fluoroquinolone (mortality rate at 60 days: 20 vs. 69.6%, p < 0.001; median survival time: not reached vs. 29.5 days, p < 0.001). The IPTW adjusted hazard of mortality at 60 days in patients receiving azithromycin was 0.17 (95% CI 0.05-0.61). No serious adverse events were observed. CONCLUSIONS: Azithromycin was associated with improved outcomes in patients with AE-CFIP. Further studies are needed to verify this finding (Clinical trial JMA-IIA00095).

Algorithms Identifying Patients With Acute Exacerbation of Interstitial Pneumonia and Acute Interstitial Lung Diseases Developed Using Japanese Administrative Data.

BACKGROUND: We aimed to develop algorithms to identify patients with acute exacerbation of interstitial pneumonia and acute interstitial lung diseases using Japanese administrative data. METHODS: This single-center validation study examined diagnostic algorithm accuracies. We included patients >18 years old with at least one claim that was a candidate for acute exacerbation of interstitial pneumonia, acute interstitial lung diseases, and pulmonary alveolar hemorrhage who were admitted to our hospital between January 2016 and December 2021. Diagnoses of these conditions were confirmed by at least two respiratory physicians through a chart review. The positive predictive value was calculated for the created algorithms. RESULTS: Of the 1,109 hospitalizations analyzed, 285 and 243 were for acute exacerbation of interstitial pneumonia and acute interstitial lung diseases, respectively. As there were only five cases of pulmonary alveolar hemorrhage, we decided not to develop an algorithm for it. For acute exacerbation of interstitial pneumonia, acute interstitial lung diseases, and acute exacerbation of interstitial pneumonia or acute interstitial lung diseases, algorithms with high positive predictive value (0.82, 95% confidence interval: 0.76-0.86; 0.82, 0.74-0.88; and 0.89, 0.85-0.92, respectively) and algorithms with slightly inferior positive predictive value but more true positives (0.81, 0.75-0.85; 0.77, 0.71-0.83; and 0.85, 0.82-0.88, respectively) were developed. CONCLUSION: We developed algorithms with high positive predictive value for identifying patients with acute exacerbation of interstitial pneumonia and acute interstitial lung diseases, useful for future database studies on such patients using Japanese administrative data.

The ROX index (Index combining the respiratory rate with oxygenation) is a prognostic factor for acute respiratory distress syndrome.

BACKGROUND: There is no existing reliable and practical method for predicting the prognosis of acute respiratory distress syndrome (ARDS). OBJECTIVE: We aimed to clarify the association between the ROX index, which is calculated as the ratio of peripheral oxygen saturation divided by the fraction of inspired oxygen to the respiratory rate, and the prognosis of patients with ARDS under ventilator support. METHODS: In this single-center retrospective cohort study from prospectively collected database, eligible patients were categorized into three groups based on ROX tertiles. The primary outcome was the 28-day survival, and the secondary outcome was 28-day liberation from ventilator support. We performed multivariable analysis using the Cox proportional hazards model. RESULTS: Among 93 eligible patients, 24 (26%) patients died. The patients were divided into three groups according to the ROX index (< 7.4, 7.4-11, ≥ 11), with 13, 7, and 4 patients dying in the groups, respectively. A higher ROX index was associated with lower mortality; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 0.54[0.21-1.41], 0.23[0.074-0.72] (P = 0.011 for trend) and a higher rate of successful 28-day liberation from ventilator support; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 1.41[0.68-2.94], 2.80[1.42-5.52] (P = 0.001 for trend). CONCLUSIONS: The ROX index at 24 h after initiating ventilator support is a predictor of outcomes in patients with ARDS and might inform initiation of more advanced treatments.

The Accuracy of Japanese Administrative Data in Identifying Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

BACKGROUND: This study aimed to develop criteria for identifying patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) from Japanese administrative data and validate the pre-existing criteria. METHODS: This retrospective, multi-center validation study was conducted at eight institutes in Japan to verify the diagnostic accuracy of the disease name for AE-IPF. We used the Japanese Diagnosis Procedure Combination data to identify patients with a disease name that could meet the diagnostic criteria for AE-IPF, who were admitted to the eight institutes from January 2016 to February 2019. As a reference standard, two respiratory physicians performed a chart review to determine whether the patients had a disease that met the diagnostic criteria for AE-IPF. Furthermore, two radiologists interpreted the chest computed tomography findings of cases considered AE-IPF and confirmed the diagnosis. We calculated the positive predictive value (PPV) for each disease name and its combination. RESULTS: We included 830 patients; among them, 216 were diagnosed with AE-IPF through the chart review. We combined the groups of disease names and yielded two criteria: the criteria with a high PPV (0.72 [95% confidence interval 0.62 to 0.81]) and that with a slightly less PPV (0.61 [0.53 to 0.68]) but more true positives. Pre-existing criteria showed a PPV of 0.40 (0.31 to 0.49). CONCLUSION: The criteria derived in this study for identifying AE-IPF from Japanese administrative data show a fair PPV. Although these criteria should be carefully interpreted according to the target population, our findings could be utilized in future database studies on AE-IPF.

Clinical phenotypes from fatal cases of acute respiratory distress syndrome caused by pneumonia.

There have been no report of objective clinical characteristics or prognostic factors that predict fatal outcome of acute respiratory distress syndrome (ARDS) since the Berlin definition was published. The aim of this study is to identify clinically available predictors that distinguish between two phenotypes of fatal ARDS due to pneumonia. In total, 104 cases of Japanese patients with pneumonia-induced ARDS were extracted from our prospectively collected database. Fatal cases were divided into early (< 7 days after diagnosis) and late (≥ 7 days) death groups, and clinical variables and prognostic factors were statistically evaluated. Of the 50 patients who died within 180 days, 18 (36%) and 32 (64%) were in the early (median 2 days, IQR [1, 5]) and late (median 16 days, IQR [13, 29]) death groups, respectively. According to multivariate regression analyses, the APACHE II score (HR 1.25, 95%CI 1.12-1.39, p < 0.001) and the disseminated intravascular coagulation score (HR 1.54, 95%CI 1.15-2.04, p = 0.003) were independent prognostic factors for early death. In contrast, late death was associated with high-resolution computed tomography (HRCT) score indicating early fibroproliferation (HR 1.28, 95%CI 1.13-1.42, p < 0.001) as well as the disseminated intravascular coagulation score (HR 1.24, 95%CI 1.01-1.52, p = 0.039). The extent of fibroproliferation on HRCT, and the APACHE II scores along with coagulation abnormalities, should be considered for use in predictive enrichment and personalized medicine for patients with ARDS due to pneumonia.

[Solid malignancy in patients who received cyclosporine for fibrosing interstitial pneumonia].

OBJECTIVE: Since more solid malignancies are observed in transplant recipients treated with cyclosporine (CsA) than in healthy persons. We sought to describe the incidence of malignancy in patients treated with CsA for fibrosing interstitial pneumonia. METHODS: We prospectively reviewed 43 patients who received CsA and prednisolone for fibrosing interstitial pneumonia over 180 days at our hospital between April 2004 and October 2008. The duration of CsA treatment was 632 +/- 364 days. RESULTS: Malignancy developed in 6 (14.0%) patients. Time to diagnosis after medical intervention ranged from 394 days to 1325 days (mean, 783 days). Non-small cell lung cancer was diagnosed in 4 cases. These were discovered by routine computed tomography in all cases. Hepatocellular carcinoma and gastric cancer were each diagnosed in 1 case, respectively. Incidence of malignancy tended to be higher in patients who had been treated with CsA for 567 days or more than in those who had been treated for less than 567 days, but this was not statistically significant. CONCLUSION: Our results highlight the need for close follow-up for patients who receive CsA for over 2 years. This could lead to cancer detection at an early stage.

The effects of switching EGFR-TKI treatments for non-small cell lung cancer because of adverse events.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat patients with non-small cell lung cancer (NSCLC) and EGFR driver mutations. Although some patients discontinued these treatments because of adverse events, it is unclear whether switching EGFR-TKI because of adverse events provides a benefit. METHODS: This retrospective study evaluated data from 22 patients with EGFR mutation-positive NSCLC who received at least two EGFR-TKIs that were switched because of adverse events (March 2011 to September 2017). Progression-free survival 2 (PFS2) was defined as the time from starting of the first EGFR-TKI treatment to disease progression during the second EGFR-TKI treatment. RESULTS: Seventeen patients received gefitinib as the first EGFR-TKI treatment, while four patients received afatinib and one patient received erlotinib. The median time to failure of the first EGFR-TKI treatment was 1.6 months. The EGFR-TKIs were switched because of hepatotoxicity (n = 16), interstitial lung disease (n = 3), and other reasons (n = 3). The median washout period was 1.1 months. Seventeen patients received erlotinib as the second EGFR-TKI treatment, while three patients received gefitinib and two patients received afatinib. The median PFS for the second EGFR-TKI treatment was 15.2 months. The median PFS2 was 17.7 months and the median overall survival was 32.8 months. CONCLUSIONS: Switching EGFR-TKIs because of adverse events provided a clinical benefit for patients with EGFR mutation-positive NSCLC. Appropriate judgment regarding switching from one EGFR-TKI to another may improve the performance status and prognosis of patients with EGFR mutation-positive NSCLC.

A Scoring System with High-Resolution Computed Tomography to Predict Drug-Associated Acute Respiratory Distress Syndrome: Development and Internal Validation.

Drugs can cause acute respiratory distress syndrome (ARDS). However, there is no established clinical prediction rule for drug-associated ARDS (DARDS). We aimed to develop and validate a scoring system for DARDS prediction. We analysed data collected from a prospective, single-centre, cohort study that included ARDS patients. The ARDS diagnosis was based on the American-European Consensus Conference or Berlin definition. Drug-associated acute lung injury (DALI) was defined as previous exposure to drugs which cause ALI and presence of traditional risk factors for ALI. High-resolution computed tomography (HRCT; indicating extent of lung damage with fibroproliferation), Acute Physiology and Chronic Health Evaluation (APACHE) II, and disseminated intravascular coagulation (DIC; indicating multiorgan failure) scores and PaO2/FiO2 were evaluated for their ability to predict DARDS. Twenty-nine of 229 patients had DARDS. The HRCT, APACHE II, and DIC scores and PaO2/FiO2 were assessed. The model-based predicted probability of DARDS fitted well with the observed data, and discrimination ability, assessed through bootstrap with an area under the receiver-operating curve, improved from 0.816 to 0.875 by adding the HRCT score. A simple clinical scoring system consisting of the APACHE II score, PaO2/FiO2, and DIC and HRCT scores can predict DARDS. This model may facilitate more appropriate clinical decision-making.