Angiotensin-(1-7) attenuates SARS-CoV2 spike protein-induced interleukin-6 and interleukin-8 production in alveolar epithelial cells through activation of Mas receptor.

BACKGROUND: SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an inflammatory process. Angiotensin-(1-7) may have an anti-inflammatory effect through activation of Mas receptor. This study aims to investigate whether SARS-CoV-2 SP can induce inflammation through ACE2 in the alveolar epithelial cells which can be modulated through angiotensin-(1-7)/Mas receptor axis. METHODS: HPAEpiC were treated with SARS-CoV-2 SP in the presence or absence of ACE2 antagonist-dalbavancin and Mas receptor agonist-angiotensin-(1-7). Proinflammatory cytokine production (IL-6 and IL-8) were measured at mRNA and protein levels. MAP kinase phosphorylation and transcription factor activation was determined by Western Blot. Mas receptor was blocked by either antagonist (A779) or knockdown (specific SiRNA). Experiments were replicated using A549 cells. FINDINGS: SARS-CoV-2 SP (5 µg/mL) significantly induced MAP kinase (ERK1/2) phosphorylation, downstream transcription factor (activator protein-1, AP-1) activation and cytokine production (IL-6 and IL-8) at both mRNA and protein levels. Pretreatment with dalbavancin (10 µg/mL), or angiotensin-(1-7) (10 µM) significantly reduced ERK1/2 phosphorylation, AP-1 activation, and cytokine production. However, these angiotensin-(1-7)-related protective effects were significantly abolished by blocking Mas receptor with either antagonist (A799,10 µM) or SiRNA knockdown. INTERPRETATION: SARS-CoV-2 SP can induce proinflammatory cytokine production, which can be inhibited by either ACE2 antagonist or Mas receptor agonist-angiotensin-(1-7). Angiotensin-(1-7)-related protective effect on cytokine reduction can be abolished by blocking Mas receptor. Our findings suggest that ACE2/angiotensin-(1-7)/Mas axis may serve as a therapeutic target to control inflammatory response triggered by SARS-CoV-2 SP.

Body composition modify the association between ambient particulate matter and lung function among asthma patients.

The effect of ambient PM10 and PM2.5 on lung function modified by body muscle and adipose tissue is not fully understood at present. Our aims were to investigate the association between seasonal average air pollutants and lung function in asthmatic patients modified by body composition indicators. In this cross-sectional study, we recruited 914 doctor-diagnosed asthmatic patients, and performed interaction and stratified analysis using the median values of total body muscle (TBM), total body fat (TBF), and percentage body fat (PBF) as well as body mass index (BMI) =25 as the cutoff points of the high/low body composition groups. The adjusted R2 values of the developed LUR models of PM2.5 and PM10 were 91.4% and 90.5% and also verified by cross-validation, respectively. After adjusting for confounding factors, we found that TBM significantly modified the association between PM10 and lung function among asthma patients (interaction P value <0.05). In the low TBM group, seasonal average concentrations of PM10 estimated by the LUR model increased by 10 µg/m3, and negative associations with lung function indicators were observed. For obese patients with BMI>25 and high TBF, the increase in PM10 was associated with the decrease in lung function. The asthma patients with obesity and low total body muscle were more susceptible to adverse effects of PM10 on lung function.

Temporal changes in biomarkers in individuals with and without acute mountain sickness following rapid ascent.

BACKGROUND: Field studies have reported conflicting results regarding changes in biomarkers at high altitude. This study measured temporal changes in biomarkers and compared the differences between individuals with and without acute mountain sickness (AMS). MATERIALS AND METHODS: This study included 34 nonacclimatized healthy participants. Ten-milliliters of blood were collected at four time points: 3 days before ascent (T0), on two successive nights at 3150 m (T1 and T2), and 2 days after descent (T3). Participants were transported by bus from 555 m to 3150 m within 3 hours. AMS was diagnosed using the self-reported Lake Louise Scoring (LLS) questionnaire. RESULTS: Compared with T0, significant increases in E-selectin and decreases in vascular endothelial growth factor (VEGF) levels were observed at high altitude. Significantly increased C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and S100 calcium-binding protein B (S100B) levels were observed at T2, and significantly decreased vascular cell adhesion molecule-1 (VCAM-1) levels were observed at T3. Eighteen (53%) participants developed AMS. Changes in E-selectin, CRP, MCP-1, and S100B levels were independent of AMS. Relative to individuals without AMS, those with AMS had significantly higher atrial natriuretic peptide (ANP) and VCAM-1 levels and lower plasminogen activator inhibitor-1 (PAI-1) levels at T1 and higher brain natriuretic peptide and lower VEGF and PAI-1 levels at T3. LLSs were positively correlated with ANP and VCAM-1 levels and negatively correlated with PAI-1 levels measured at T1. CONCLUSIONS: After acute ascent, individuals with and without AMS exhibited different trends in biomarkers associated with endothelial cell activation and natriuretic peptides.

Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of pulmonary sarcoidosis: A 9-year experience at a single center.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is valuable for diagnosing pulmonary sarcoidosis. We aimed to evaluate the diagnostic yield of EBUS-TBNA and cytology in sarcoidosis during the first 9 years at our institution. METHODS: Patients who underwent EBUS-TBNA for suspected sarcoidosis between January 2011 and November 2019 were identified retrospectively. EBUS-TBNA was performed with rapid on-site cytological evaluation of the samples. The final diagnosis was based on the pathology and/or cytology results, radiologic features, and clinical follow-up findings. The yield rate was analyzed annually. RESULTS: Eighty patients underwent 83 EBUS-TBNA procedures for suspected sarcoidosis. In total, 136 lymph nodes were sampled. The mean number of lymph node stations sampled was 2.0 ± 0.6; the mean number of needle passes per lymph node was 3.5 ± 0.8. Sixty-five patients were diagnosed with sarcoidosis, with a total of 68 procedures. Nonnecrotizing granulomatous inflammation was detected in the EBUS-TBNA samples from 49/68 procedures (yield rate: 72.1%). Of 19 patients with sarcoidosis who did not obtain a pathological diagnosis with EBUS-TBNA, epithelioid cells and/or multinuclear giant cells suggestive of granulomatous inflammation were detected in five. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) for pathological diagnosis of sarcoidosis using EBUS-TBNA were 72.1%, 100%, 100%, and 24.0%, respectively. On using cytology, the sensitivity and NPV increased to 79.4% and 26.3%, respectively. The yield rate did not increase until 2016. CONCLUSION: EBUS-TBNA is useful for diagnosing sarcoidosis. Cytology resulted in an additional yield rate of 7.3%, which improved as the number of cases increased.

Obstructive sleep apnea in young Asian adults with sleep-related complaints.

This study aimed to investigate the proportion of young OSA adults with sleep-related complaints in a sleep center, affiliated with a tertiary medical center for over a decade. This study presents a chronicle change in the numbers of young adults receiving polysomnography (PSG) and young patients with OSA from 2000 to 2017. We further analyzed 371 young patients with OSA among 2378 patients receiving PSG in our sleep center from 2016 to 2017 to capture their characteristics. Young adults constituted a substantial and relatively steady portion of examinees of PSG (25.1% ± 2.8%) and confirmed OSA cases (19.8 ± 2.4%) even though the total numbers increased with the years. Young adults with OSA tend to be sleepier, have a greater body mass index, and have a higher percentage of cigarette smoking and alcohol consumption. They also complained more about snoring and daytime sleepiness. They had a higher apnea-hypopnea index on average and experienced more hypoxemia during their sleep, both in terms of duration and the extent of desaturation. Even though the prevalence of comorbidities increased with age, hypertension in young male adults carried higher risks for OSA. Young adults with OSA have constituted a relatively constant portion of all confirmed OSA cases across time. The young adults with OSA were heavier, more symptomatic, and with more severe severity.Clinical trial: The Institutional Review Board of Taipei Veterans General Hospital approved the study (VGHIRB No. 2018-10-002CC). The study is registered with ClinicalTrials.gov, number NCT03885440.

Bronchoalveolar lavage fluid analysis and mortality risk in systemic lupus erythematosus patients with pneumonia and respiratory failure.

BACKGROUND: Our aim was to characterize etiologic diagnoses obtained from bronchoalveolar lavage fluid (BALF) and blood specimens, and to identify risk factors for mortality in systemic lupus erythematosus (SLE) patients with pneumonia and respiratory failure. METHODS: We conducted a retrospective analysis of SLE patients with pneumonia and respiratory failure. Clinical characteristics, laboratory profiles, and microbiology in BALF and blood samples were evaluated. We performed univariable analyses to identify mortality risk factors. RESULTS: All 24 patients (F:M = 21:3, median age 46.5 years; disease duration 11 years) received mechanical ventilation (median duration: 11 days). Pathogens identified in BALF included Pneumocystis jiroveci (12 patients [50%]), cytomegalovirus (CMV, 7 patients [29.2%]), and bacteria (11 patients [45.8%]). Thirteen patients (54.2%) yielded pathogens in blood (CMV in 8 patients [33.3%] and Escherichia coli in 5 patients [20.8%]). Eight developed septic shock, and 9 died within 30 days. Univariable analysis identified thrombocytopenia (odds ratio [OR]: 8.0, 95% confidence interval [CI]: 1.23-52.25), bacteremia within 30 days before or after endotracheal intubation (OR: 8.0, 95% CI: 1.23-52.5), and P. jiroveci pneumonia (PJP, OR: 7.0, 95% CI: 1.04-46.95) as risk factors for 30-day mortality. Kaplan-Meier analysis confirmed an increased risk of 30-day mortality with thrombocytopenia and bacteremia. CONCLUSION: There are high prevalence rates of PJP and CMV infections as evidenced by BALF analyses in SLE patients with pneumonia and respiratory failure. BALF analysis can facilitate rescue therapy per pathogen. Thrombocytopenia, bacteremia, and PJP in SLE patients can increase their 30-day mortality, so warrant early and aggressive treatments.

Clinical usefulness of bronchoalveolar lavage in patients with interstitial lung diseases: a pilot study.

BACKGROUND: Bronchoalveolar lavage (BAL) is a useful tool in the diagnostic work-up of patients with interstitial lung diseases (ILDs). In this prospective study, we investigated the clinical usefulness of BAL in patients with ILD radiographically. METHODS: The enrolled patients were classified into outpatient department (OPD), and inpatients groups who was admitted to general ward (GW) or intensive care unit (ICU) groups based on the time when BAL done. The clinical usefulness of BAL was defined as a new diagnosis established and/or treatment significantly changed. The clinical usefulness of BAL among the three groups of patients and the patients divided by underlying diseases was compared using the χ2 test with or without Fisher's exact test. RESULTS: Among our 184 patients, there were 37 in OPD group, 86 in GW group and 61 in ICU group. The final diagnoses were infectious in 23, non-infectious in 102, mixed etiologies in 19, and non-diagnostic in 40 patients. The diagnostic yields (revised diagnosis after BAL) of BAL among ICU patients, GW patients and OPD patients were 60.6%, 69.7% and 21.6%, respectively (P<0.001), and was 57.1% in total patients. The diagnostic yields of BAL among patients with cancer, organ transplantation and collagen vascular disease were statistically different (P=0.009). CONCLUSIONS: BAL is of use in establishing a diagnosis of ILD and is mandatary especially in the admitted patients with ILD because diagnostic yield was relatively higher in admitted patients than in OPD patients. In addition, BAL should be done more early in the admitted patients with malignancy, stem cell and/or organ transplantation and collagen vascular disease especially when they showed poor response to initial medications.

Prolonged use of noninvasive positive pressure ventilation after extubation among patients in the intensive care unit following cardiac surgery: The predictors and its impact on patient outcome.

This retrospective, observational cohort study aimed to determine the independent risk factors and impact of prolonged non-invasive positive pressure ventilation (NIPPV) after extubation among patients in the intensive care unit following cardiac surgery. Patients who received prophylactic NIPPV after extubation were categorized into prolonged (NIPPV duration >3 days, n = 83) and non-prolonged groups (NIPPV duration ≤3 days, n = 105). The perioperative characteristics and hospital outcomes were recorded. The multivariate analyses identified the preoperative residual volume/total lung capacity (RV/TLC) ratio (adjusted odds ratio [AOR]: 1.10; 95% CI:1.01-1.19, p = 0.022) and postoperative acute kidney injury (AKI) with Kidney Disease Improving Global Outcomes (KDIGO) stage 2-3, 48 h after surgery (AOR: 3.87; 95% CI:1.21-12.37, p = 0.023) as independent predictors of prolonged NIPPV. Patients with both RV/TLC ratio > 46.5% and KDIGO stage 2-3 showed a highly increased risk of prolonged NIPPV (HR 27.17, p = 0.010), which was in turn associated with higher risk of postoperative complications and prolonged ICU and hospital stays. Preoperative RV/TLC ratio and postoperative AKI could identify patients at higher risk for prolonged NIPPV associated with poor outcomes. These findings may allow early recognition of patients who are at a higher risk for prolonged NIPPV, and help refine the perioperative management and critical care.

The usefulness of prophylactic use of acetazolamide in subjects with acute mountain sickness.

BACKGROUND: The mechanisms of acetazolamide (ACZ) in the prophylaxis of acute mountain sickness (AMS) remain unclear. This study evaluated the changes in physiological variables of sleep and heart rate variability (HRV) in subjects with earlier history of AMS who underwent prophylactic treatment of ACZ. METHODS: Nonacclimatized healthy subjects were transported using a bus from 555 m to 3150 m within 3 hours. Polysomnography (PSG) was performed 3 days before ascent (T0), for two consecutive nights at 3150 m (T1 and T2), and 2 days after descent (T3). HRV was measured before sleep and after awakening from T0 to T3. AMS was diagnosed using a self-reported Lake Louise score questionnaire. Subjects found confirmed to have AMS were enrolled in this study. The physiological variables and HRV were compared in AMS subjects without (control group) and with prophylactic ACZ (prophylactic ACZ group). RESULTS: Thirteen AMS subjects were enrolled. The PSG results were analyzed in eight and HRV were analyzed in nine of the 13 subjects. The prophylactic use of ACZ in the subjects with a history of AMS significantly improved sleep efficiency (p = 0.012) and awakening percentages (p = 0.017) at T1, significantly higher levels of arterial oxygen saturation (SaO2) and lower values of partial pressure end-tidal carbon dioxide tension (PETCO2) at four time points. Furthermore, they had a higher rapid eye movement sleep percentage (p = 0.05) at T2. Prophylactic ACZ treatment significantly increased the normalized unit of high frequency at T1 after awakening (p = 0.028). CONCLUSION: Significantly higher quality of sleep, higher SaO2 during sleep, and lower PETCO2 at high altitude were found in the subjects with a history of AMS using prophylactic ACZ before rapid ascent. ACZ may accelerate the acclimatization process for rapid ascents to high altitudes by increasing parasympathetic tone based on HRV analyses.

Cytomegaloviral or Pneumocystis Jiroveci Pneumonia Increases Mortality in Systemic Lupus Erythematosus Patients with Pulmonary Hemorrhage: Evidence from Bronchoalveolar Lavage Fluid.

OBJECTIVE: To evaluate the role of cytomegaloviral or Pneumocystis jiroveci pneumonia (CMV/PJP) in systemic lupus erythematosus (SLE) patients with pulmonary hemorrhage (PH). METHODS: We retrospectively examined hospital records for 27 SLE patients with PH who received bronchoalveolar lavage fluid (BALF) analyses. Clinical profile and mortality rates were compared between groups with and without CMV/PJP. Risk factors for PH-related mortality were analyzed. RESULTS: Among 27 SLE patients with PH, 15 had pathogens from BALF samples, and 8 had CMV/PJP. Although CMV/PJP was treated, the RR for 90- and 180-day mortality rates of SLE patients with CMV/PJP were higher than those without these infections (5.94, 95% CI 1.44-24.48; 7.13, 95% CI 1.81-28.06, respectively). Risk factors for 90- and 180-day mortality were presence of CMV/PJP (OR 14.2, 95% CI 1.83-109.9; OR 25.5, 95% CI 2.91-223.3, respectively) and use of pulse methylprednisolone for PH treatment (OR 12.0, 95% CI 1.48-97.2; OR 8.5, 95% CI 1.13-63.9, respectively). Factors increasing the 90-day mortality rate were duration of mechanical ventilation exceeding 14 days (OR 11.1, 95% CI 1.11-112.0) and use of aggressive immunosuppression close to PH onset (OR 7.56, 95% CI 1.09-52.4). Three of the 7 patients receiving aggressive immunosuppression died with the presence of CMV/PJP. CONCLUSION: Owing to the high prevalence of CMV/PJP and its association with mortality, routine BALF analysis is recommended for all suitable SLE patients with PH. Use of aggressive immunosuppression does not benefit SLE patients with opportunistic infections during PH attack.

A simplified prevention bundle with dual hand hygiene audit reduces early-onset ventilator-associated pneumonia in cardiovascular surgery units: An interrupted time-series analysis.

BACKGROUND: To investigate the effect of a simplified prevention bundle with alcohol-based, dual hand hygiene (HH) audit on the incidence of early-onset ventilation-associated pneumonia (VAP). METHODS: This 3-year, quasi-experimental study with interrupted time-series analysis was conducted in two cardiovascular surgery intensive care units in a medical center. Unaware external HH audit (eHH) performed by non-unit-based observers was a routine task before and after bundle implementation. Based on the realistic ICU settings, we implemented a 3-component bundle, which included: a compulsory education program, a knowing internal HH audit (iHH) performed by unit-based observers, and a standardized oral care (OC) protocol with 0.1% chlorhexidine gluconate. The study periods comprised 4 phases: 12-month pre-implementation phase 1 (eHH+/education-/iHH-/OC-), 3-month run-in phase 2 (eHH+/education+/iHH+/OC+), 15-month implementation phase 3 (eHH+/education+/iHH+/OC+), and 6-month post-implementation phase 4 (eHH+/education-/iHH+/OC-). RESULTS: A total of 2553 ventilator-days were observed. VAP incidences (events/1000 ventilator days) in phase 1-4 were 39.1, 40.5, 15.9, and 20.4, respectively. VAP was significantly reduced by 59% in phase 3 (vs. phase 1, incidence rate ratio [IRR] 0.41, P = 0.002), but rebounded in phase 4. Moreover, VAP incidence was inversely correlated to compliance of OC (r2 = 0.531, P = 0.001) and eHH (r2 = 0.878, P < 0.001), but not applied for iHH, despite iHH compliance was higher than eHH compliance during phase 2 to 4. Compared to eHH, iHH provided more efficient and faster improvements for standard HH practice. The minimal compliances required for significant VAP reduction were 85% and 75% for OC and eHH (both P < 0.05, IRR 0.28 and 0.42, respectively). CONCLUSIONS: This simplified prevention bundle effectively reduces early-onset VAP incidence. An unaware HH compliance correlates with VAP incidence. A knowing HH audit provides better improvement in HH practice. Accordingly, we suggest dual HH audit and consistent bundle performance does matter in quality-of-care VAP prevention.

Effects of rapid ascent on the heart rate variability of individuals with and without acute mountain sickness.

PURPOSE: Through time- and frequency-domain analysis, we compared the effects of acute hypobaric hypoxia on the changes in heart rate variability (HRV) following night sleeping and morning awakening in individuals with and without acute mountain sickness (AMS). METHOD: Thirty-nine nonacclimatised healthy individuals were transported by bus from sea level to 3150 m within 3 h. Short-term HRV was measured two times a day-before sleeping (BS) and after awakening (AA)- at 3 days before ascent (T0), two consecutive nights at 3150 m (T1 and T2), and 2 days after descent (T3). AMS was diagnosed using the self-reported Lake Louise score questionnaire. RESULT: AMS developed in 19 of 39 participants (48.7%). At sea level, individuals had higher HRV at AA than at BS, and the trend of increased HRV at AA remained unchanged at high altitude, irrespective of AMS. At T1 BS, low-frequency power in normalised unit was significantly lower in participants with AMS than in those without AMS. Compared with those at T1 BS, the square root of the mean squared differences of successive normal-normal (NN) intervals, the number of interval differences of successive NN intervals more than 50 ms (NN50), and the proportion derived by dividing NN50 by the total number of NN intervals at T1 AA significantly increased in participants without AMS but nonsignificantly decreased in those with AMS. CONCLUSION: After rapid ascent, individuals with AMS did not demonstrate sympathetic hyperactivity but did exhibit withdrawal of cardiac vagal modulation in the morning following the first night's sleep.

Clinical Usefulness of HRCT in Assessing the Severity of Pneumocystis jirovecii Pneumonia: A Cross-sectional Study.

The aim of this study was to investigate the clinical relevance of thoracic high-resolution computed tomography (HRCT) in evaluating the severity and outcome of Pneumocystis jirovecii pneumonia (PJP) in non-AIDS immunocompromised patients.We measured mean lung attenuation (MLA) and extent of increased attenuation (EIA) of PJP lesions on thoracic HRCT in 40 non-AIDS immunocompromised patients with PJP diagnosed by demonstration of the pathogens in cytological smears of bronchoalveolar lavage fluid. The MLA and EIA of PJP lesions on thoracic HRCT were used to investigate the severity of PJP. Clinically, the severity of PJP was determined by arterial oxygen tension/fraction of inspired oxygen concentration (PaO2/FiO2) ratio, acute physiology and chronic health evaluation (APACHE) II scores, the need of mechanical ventilation, and death.MLA highly correlated with EIA of PJP lesions (ρ = 0.906, P < 0.001). MLA and EIA of PJP lesions significantly correlated with PaO2/FiO2 (ρ = -0.481 and -0.370, respectively and P = 0.007 and 0.044, respectively). When intensive care unit (ICU) admission and HRCT performed were within 2 days, MLA and EIA of PJP lesions were significantly correlated with APACHE II score (ρ = 0.791 and 0.670, respectively and P = 0.001 and 0.009, respectively). There were significant differences in the values of MLA and EIA of PJP lesions between patients with and without assisted mechanical ventilator (MLA, median and [interquartile range, IQR, 25%, 75%] -516.44 [-572.10, -375.34] vs -649.27 [-715.62, -594.01], P < 0.001 and EIA, median and [IQR 25%, 75%] 0.75 [0.66, 0.82] vs 0.53 [0.45, 0.68], P = 0.003, respectively). The data of MLA and EIA of PJP lesions had limited value in identifying survivors and non-survivors.The MLA and EIA values of PJP lesions measured on thoracic HRCT might be valuable in assessing the severity of PJP in non-AIDS immunocompromised patients, but might have limited value in predicting the mortality of the patients.

Impact of rapid ascent to high altitude on sleep.

PURPOSE: Sleep disturbance at high altitude is common in climbers. In this study, we intended to evaluate the effect of rapid ascent on sleep architecture using polysomnography (PSG) and to compare the differences between subjects with and without acute mountain sickness (AMS). METHODS: The study included 40 non-acclimatized healthy subjects completing PSG at four time points, 3 days before the ascent (T0), two successive nights at 3150 m (T1 and T2), and 2 days after the descent (T3). All subjects were transported by bus from 555 to 3150 m within 3 h. AMS was diagnosed using self-reported questionnaire of Lake Louise score. RESULTS: Twenty of 40 (50%) subjects developed AMS. At high altitude, awakening percentages increased in AMS group but changed insignificantly in non-AMS group. Arousal index and apnea/hypopnea index (AHI) increased irrespective of AMS. The increases of AHI were more evident in non-AMS group than in AMS group. Compared to subjects without AMS, those with AMS had significantly lower sleep efficiency, lower central apnea index, and longer latencies to sleep and rapid eye movement (REM) sleep at T1 and lower REM sleep percentages at T1 and T2. Subjects with older age and lower minimum arterial oxygen saturation during sleep at sea level were prone to develop AMS. CONCLUSIONS: Higher AHI did not cause more frequent awakenings and arousals at high altitude. Central sleep apneas were observed in non-AMS but not in AMS group. Subjects unacclimatized to acute hypobaric hypoxia might have delayed and less REM sleep.

The impact of concomitant pulmonary infection on immune dysregulation in Pneumocystis jirovecii pneumonia.

BACKGROUND: Concurrent infection may be found in Pneumocystis jirovecii pneumonia (PJP) of non-acquired immunodeficiency syndrome (AIDS) patients, however, its impact on immune dysregulation of PJP in non-AIDS patients remains unknown. METHODS: We measured pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-8, IL-17, monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-ß1 and IL-1 receptor antagonist (IL-1RA) and inflammatory markers including high mobility group box 1, Krebs von den Lungen-6, receptor for advanced glycation end product, advanced glycation end product, surfactant protein D in bronchoalveolar lavage fluid (BALF) and blood in 47 pure PcP and 18 mixed PJP and other pulmonary infections (mixed PJP) in non-AIDS immunocompromised patients and explored their clinical relevance. The burden of Pneumocystis jirovecii in the lung was determined by counting number of clusters of Pneumocystis jirovecii per slide and the concentration of ß-D-glucan in BALF. PJP severity was determined by arterial oxygen tension/fraction of inspired oxygen concentration ratio, the need of mechanical ventilation and death. RESULTS: Compared with pure PJP group, mixed PJP group had significantly higher BALF levels of IL-1ß, TNF-α and IL-8 and significantly higher blood levels of IL-8. The BALF ratios of TNF-α/IL-10, IL-8/IL-10, IL-1ß/IL-10, TNF-α/TGF-ß1, IL-8/TGF-ß1, IL-1ß/TGF-ß1 and IL-1ß/IL-1RA were significantly higher in mixed than in pure PJP patients. There was no significant difference in clinical features and outcome between pure and mixed PJP groups, including inflammatory biomarkers and the fungal burden. In pure PJP patients, significantly higher BALF levels of IL-8 and the ratios of IL-8/IL-10, IL-1ß/TGF-ß1, MCP-1/TGF-ß1, MCP-1/IL1RA and IL-8/TGF-ß1 were found in the patients requiring mechanical ventilation and in non-survivors. CONCLUSIONS: In summary, concurrent pulmonary infection might enhance immune dysregulation of PJP in non-AIDS immunocompromised patients, but did not affect the outcome as evidenced by morbidity and mortality. Because of limited number of cases studied, further studies with larger populations are needed to verify these issues.

The importance of pro-inflammatory and anti-inflammatory cytokines in Pneumocystis jirovecii pneumonia.

The role of pro-inflammatory and anti-inflammatory cytokines in Pneumocystis jirovecii pneumonia (PcP) of non-AIDS immunocompromised patients remains unclear. We measured the levels of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-ß1 in bronchoalveolar lavage fluid (BALF) and blood in 36 non-AIDS immunocompromised patients with PcP diagnosed by BAL and explored their clinical importance. The severity of PcP was determined by arterial oxygen tension/fraction of inspired oxygen concentration (PaO2/FiO2) ratio, the need of mechanical ventilation and the death. Twenty-five subjects without evidence of lung abnormality were included as control group. Compared with control group, PcP patients had significantly higher BALF levels of IL-1ß, TNF-α, IL-6, IL-8 and MCP-1 and significantly higher blood levels of IL-10, TGF-ß1, IL-8, IL-6 and MCP-1. For PcP patients, BALF levels of IL-8, IL-8/IL-10 ratio and IL-8/TGF-ß1 ratio and blood levels of IL-8 and IL-8/IL-10 ratio were significantly higher in the patients with PaO2/FiO2 < 200 mmHg than in those with PaO2/FiO2 > 200 mmHg. Similarly, significantly higher BALF levels of IL-8, IL-8/IL-10 ratio, IL-1ß/IL-10, IL-1ß/TGF-ß1 ratio, MCP-1/TGF-ß1 ratio and IL-8/TGF-ß1 ratio were found in the patients requiring mechanical ventilation and in non-survivors. In summary, an imbalance of pro-inflammatory and anti-inflammatory cytokines in BALF was found in PcP of non-AIDS immunocompromised patients. BALF levels of IL-8, IL-8/IL-10 ratio, IL-1ß/IL-10 ratio, IL-1ß/TGF-ß1 ratio, MCP-1/TGF-ß1 ratio and IL-8/TGF-ß1 ratio may be of value in assessing the severity of PcP and in predicting the outcome of the patients.

Statin-induced lung injury: diagnostic clue and outcome.

BACKGROUND: Statin-induced lung injury (SILI) is an uncommon but serious complication of statins. The clinical features and outcome of patients with SILI vary widely. Clinical data relevant to diagnosis and outcome of patients with SILI were investigated in this study. METHOD: Four cases of SILI diagnosed at our institute and 12 cases reported in the English literature from 1995 to 2010 were studied. The patients were further divided into favourable and unfavourable outcome groups and compared. RESULTS: Compared with the 12 previously reported cases, fever (p=0.008) and consolidation (p=0.027) were more common and duration of statin treatment was significantly shorter (p=0.030) in our patients. Foamy alveolar macrophages in bronchoalveolar lavage fluid (BALF) were found in our four patients. Patients with cough (p=0.024), fever (p=0.026) and alveolar infiltrates (p=0.036), especially ground-glass opacity (GGO) (p=0.001) shown on thoracic high-resolution CT (HRCT), had a favourable outcome. Conversely, those with fibrosis shown on HRCT (p=0.008) had an unfavourable outcome. Stepwise logistic regression analysis demonstrated that cough (p=0.011), fever (p=0.005), and alveolar infiltrates (p=0.017), GGO (p<0.001) and fibrosis (p=0.002) shown on thoracic HRCT were independent factors affecting the outcome of SILI. CONCLUSIONS: For patients with SILI, pulmonary phospholipidosis, as shown by foamy alveolar macrophages in BALF, may be valuable in diagnosis, and clinical symptoms and thoracic HRCT findings are of value in predicting the outcome.

The role of total bile acid in oral secretions in ventilator-associated pneumonia.

PURPOSE: The aim of this study was to investigate the role of inflammatory biomarkers and total bile acid (TBA) in oral secretions in the development of ventilator-associated pneumonia (VAP). MATERIALS: This prospective study was conducted in an intensive care unit. Oral secretions were collected from mechanically ventilated patients who met the selection criteria for VAP prevention protocol. The levels of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor α, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, C-reactive protein, surfactant protein D, and TBA in oral secretions were measured and compared between the patients with and those without VAP. RESULTS: Thirty-nine patients with and 39 patients without VAP were studied. The levels of inflammatory biomarkers in oral secretions showed no significant difference between the 2 groups. However, the patients with VAP had significantly higher values of TBA in oral secretions than did those without VAP (median and 25th-75th interquartile range, 9.59 and 1.37-24.66 µmol/L vs 2.74 and 0.00-8.22 µmol/L; P < .003). No significant correlations were found between TBA and inflammatory biomarkers in oral secretions. CONCLUSIONS: Duodenogastroesophageal reflux as evidenced by the presence of TBA in oral secretions is common in mechanically ventilated patients and may play a role in the development of VAP.

Clinical importance of bronchoalveolar lavage fluid and blood cytokines, surfactant protein D, and Kerbs von Lungren 6 antigen in idiopathic pulmonary alveolar proteinosis.

OBJECTIVE: To investigate the clinical importance of cytokines, surfactant protein D (SFTPD, formerly SP-D), and Kerbs von Lungren 6 antigen (KL-6) in bronchoalveolar lavage fluid (BALF) and blood in patients with idiopathic pulmonary alveolar proteinosis (iPAP). PARTICIPANTS AND METHODS: Patients with iPAP diagnosed by characteristic cytopathologic examination of BALF and pathologic examination of transbronchial lung biopsy specimens or open lung biopsy specimens were enrolled in the study from January 1, 1995, through June 30, 2005. To investigate the clinical importance of cytokines, SFTPD, and KL-6 in iPAP, we measured tumor necrosis factor superfamily, member 2 (TNF, formerly TNF-alpha) and interleukin (IL) 1beta in BALF and IL-6, IL-10, IL-8, chemokine (C-C motif) ligand 4 (CCL4, formerly MIP-1beta), chemokine (C-C motif) ligand 2 (CCL2, formerly MCP-1), SFTPD, and KL-6 in both BALF and blood in 15 patients with iPAP and 48 patients with interstitial lung diseases (diseased controls) (including 20 with interstitial pneumonitis associated with collagen vascular diseases, 13 with idiopathic pulmonary fibrosis, and 15 with sarcoidosis) and 20 individuals without pulmonary diseases (lung controls). RESULTS: Patients with iPAP had significantly higher levels of TNF, IL-6, IL-8, CCL4, CCL2, SFTPD, and KL-6 in BALF than did lung controls and had significantly higher levels of CCL4, CCL2, SFTPD, and KL-6 levels in BALF than did diseased controls. Patients with iPAP had significantly higher levels of IL-10, IL-8, CCL2, SFTPD, and KL-6 in blood than did lung controls and significantly higher levels of KL-6 in blood than did diseased controls. Levels of KL-6 both in BALF and blood were significantly correlated with serum lactate dehydrogenase level, arterial oxygen tension, and alveolar-arterial gradient in partial pressure of oxygen, the severity markers for iPAP, and were significantly higher in patients with iPAP who required subsequent therapeutic lung lavage. CONCLUSION: Patients with iPAP had elevated levels of SFTPD, KL-6, and cytokines in both BALF and blood. Elevated levels of KL-6 in both BALF and blood may be valuable in reflecting disease severity of patients with iPAP and in determining the need for therapeutic lung lavage.

Intermittent suction of oral secretions before each positional change may reduce ventilator-associated pneumonia: a pilot study.

BACKGROUND: That ventilator-associated pneumonia (VAP) can be reduced by continuous and/or intermittent subglottic suction highlights the importance of clearance of oropharyngeal secretions. We prospectively evaluated the usefulness of intermittent suction of oral secretions before each positional change in reducing VAP. METHODS: A time-sequence nonrandomized intervention design was used. The study consisted of a 9-month observation phase (control group, 237 patients), a 6-month education phase, followed by a 7-month intervention phase (studied group, 227 patients). The occurrence of VAP, duration of mechanical ventilation, length of intensive care unit (ICU) stay, and mortality were recorded. RESULTS: VAP occurred less frequently in the studied group (6 of 227 patients, 2.6%) than in the control group (26 of 237 patients, 11.0%; P < 0.001). The incidence rate of VAP in control and studied groups was 6.51 and 2.04 per 1000 ventilator days, respectively (P = 0.002). For VAP patients, the ventilator days were 28.8 +/- 17.2 days and 20.2 +/- 4.0 days (P = 0.009), respectively, and the length of ICU stay was 27.6 +/- 17.0 days and 20.3 +/- 4.0 days (P = 0.012), respectively, in the control and studied groups. Intermittent suction of oral secretions before each positional change was the only independent factor responsible for a decrease of VAP in the studied group after stepwise logistic regression analysis (P = 0.003). CONCLUSIONS: Intermittent suction of oral secretions before each positional change may reduce VAP occurrence in ICU patients.