Elevated peripheral blood monocyte count is associated with prolonged postoperative hospitalization and functional decline in patients with interstitial lung diseases undergoing surgical lung biopsy.

OBJECTIVE: Monocyte count and red cell distribution width (RDW) have shown prognostic potential in patients with fibrotic lung diseases. Their kinetics and prognostic usefulness of peripheral blood indices in patients with interstitial lung diseases (ILDs) undergoing surgical lung biopsy for diagnostic reasons have not been studied. PATIENTS AND METHODS: We retrospectively included consecutive patients with ILD who underwent surgical lung biopsy for diagnostic purposes Between 07/11/2019 and 11/10/2022. RESULTS: Fifty-five (n=55) patients were included in the study. Median age was 65.0 years (95% CI: 63.0 to 66.0). Postoperative peripheral blood monocyte count on Day 1 was significantly higher compared to preoperative, perioperative, and postoperative values on Day 90 (repeated measures ANOVA, p<0.0001). Patients in the high postoperative monocyte count group had significantly increased length of postoperative hospital stay [Mann-Whitney test, p=0.007] and significantly lower Forced Vital Capacity (FVC)% predicted 3 months after surgery [Mann-Whitney test, p=0.029] compared to patients in the low postoperative monocyte count group. Postoperative RDW on Day 90 was significantly higher compared to preoperative, perioperative and postoperative-Day 1 RDW (repeated measures ANOVA, p=0.008, p=0.006, p<0.0001, respectively). Patients in the high postoperative RDW group did not have increased hospital stay (Mann-Whitney test, p=0.49) or decreased FVC% predicted at 3 months compared to patients in the low postoperative RDW group (Mann-Whitney test, p=0.91). CONCLUSIONS: Peripheral blood monocyte count could be a prognostic biomarker for patients with ILDs undergoing diagnostic surgical lung biopsies. RDW does not seem to represent an acute phase biomarker but seems to increase over time following disease progression. Larger studies are urgently required.

Pharmacological treatment of stable COPD: need for a simplified approach.

Chronic obstructive pulmonary disease (COPD) is one of the most common diseases worldwide. Although different guidelines regarding therapeutic algorithms exist, the most widely adopted approach is the one suggested by the Global Initiative in Chronic Obstructive Lung Disease in which patients are stratified according to their dyspnea severity and their exacerbation history during the previous year. This combined assessment of COPD, which takes into consideration all aforementioned characteristics of COPD patients as well as the number of blood eosinophils, results in a proposed therapeutic algorithm which is complex and hard to memorize. This complexity is probable one of the causes that most health care professionals are not adherent to the guidelines when treating COPD patients. Here, we propose a simplified therapeutic algorithm for the treatment of COPD patients taking into consideration the current evidence on the use of bronchodilators and inhaled corticosteroids.

Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: Comparison with different sputum phenotypes.

BACKGROUND: According to induced sputum cell count, four different asthma phenotypes have been recognized (eosinophilic, neutrophilic, mixed and paucigranulocytic). The aim of this study was to detect functional and inflammatory characteristics of patients with paucigranulocytic asthma. METHODS: A total of 240 asthmatic patients were categorized into the four phenotypes according to cell counts in induced sputum. All patients underwent pulmonary function tests, and measurement of fraction of exhaled nitric oxide (FeNO). The levels of IL-8, IL-13 and eosinophilic cationic protein (ECP) were also measured in sputum supernatant. Treatment, asthma control and the presence of severe refractory asthma (SRA) were also recorded. RESULTS: Patients were categorized into the four phenotypes as follows: eosinophilic (40%), mixed (6.7%), neutrophilic (5.4%) and paucigranulocytic (47.9%). Although asthma control test did not differ between groups (P=.288), patients with paucigranulocytic asthma had better lung function (FEV1 % pred) [median (IQR): 71.5 (59.0-88.75) vs 69.0 (59.0-77.6) vs 68.0 (60.0-85.5) vs 80.5 (69.7-95.0), P=.009] for eosinophilic, mixed, neutrophilic and paucigranulocytic asthma, respectively, P=.009). SRA occurred more frequently in the eosinophilic and mixed phenotype (41.6% and 43.7%, respectively) and less frequently in the neutrophilic and paucigranulocytic phenotype (25% and 21.7%, respectively, P=.01). FeNO, ECP and IL-8 were all low in the paucigranulocytic, whereas as expected FeNO and ECP were higher in eosinophilic and mixed asthma, while IL-8 was higher in patients with neutrophilic and mixed asthma (P<.001 for all comparisons). Interestingly, 14.8% of patients with paucigranulocytic asthma had poor asthma control. CONCLUSION: Paucigranulocytic asthma most likely represents a "benign" asthma phenotype, related to a good response to treatment, rather than a "true" phenotype of asthma. However, paucigranulocytic patients that remain not well controlled despite optimal treatment represent an asthmatic population that requires further study for potential novel targeted interventions.

Sputum interleukin-13 as a biomarker for the evaluation of asthma control.

BACKGROUND: Asthma control refers to the extent to which the manifestations of asthma have been reduced or eradicated by treatment. Interleukin-13 (IL-13) has a central role in Th2 response and serves as a possible therapeutic target in uncontrolled asthma. Fraction of exhaled nitric oxide (FeNO) and sputum eosinophils have modest performance in the evaluation of asthma control. OBJECTIVE: To assess the diagnostic performance of sputum IL-13 for the evaluation of asthma control and furthermore to investigate the performance of sputum eosinophils and FeNO. METHODS: One hundred and seventy patients with asthma were studied. All subjects underwent assessment of asthma control by asthma control test (ACT), lung function tests, FeNO measurement and sputum induction for cell count identification and IL-13 measurement in supernatants. RESULTS: IL-13 (pg/mL) levels in sputum supernatant differed significantly among patients with well-controlled asthma and those with not well-controlled asthma [median IQR 78 (66-102) vs. 213 (180-265), P < 0.001]. Receiver operating characteristic (ROC) analysis showed that, for the whole study population, the diagnostic performance of IL-13 was superior to both sputum eosinophils and FeNO levels [area under the curve (AUC) 0.92, 95% CI 0.87 to 0.95 vs. AUC 0.65, 95% CI 0.58 to 0.72 vs. AUC 0.65, 95% CI 0.55 to 0.72, respectively]. CONCLUSION: The diagnostic performance of sputum IL-13 was superior to both sputum eosinophils and FeNO levels for the identification of well-controlled asthma. Sputum IL-13 levels could serve as a useful biomarker for asthma control assessment.

Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma.

Clara cell secretory protein (CC16) is associated with Th2 modulation. Surfactant protein D (SPD) plays an important role in surfactant homeostasis and eosinophil chemotaxis. We measured CC16 and SPD in sputum supernatants of 84 asthmatic patients and 12 healthy controls. In 22 asthmatics, we additionally measured CC16 and SPD levels in BAL and assessed smooth muscle area (SMA), reticular basement membrane (RBM) thickness, and epithelial detachment (ED) in bronchial biopsies. Induced sputum CC16 and SPD were significantly higher in patients with severe asthma (SRA) compared to mild-moderate and healthy controls. BAL CC16 and SPD levels were also higher in SRA compared to mild-moderate asthma. CC16 BAL levels correlated with ED, while SPD BAL levels correlated with SMA and RBM. Severity represented a significant covariate for these associations. CC16 and SPD levels are upregulated in SRA and correlate with remodeling indices, suggesting a possible role of these biomarkers in the remodeling process.

Levels of prostaglandin E(2) and Cysteinyl-leukotrienes in sputum supernatant of patients with asthma: the effect of smoking.

BACKGROUND: Smoking is associated with worse asthma outcomes and may modify airway inflammation. Such modification may be mediated through an effect on prostaglandin E(2) (PGE(2)) and cysteinyl leukotrienes (Cyst-LTs). OBJECTIVE: We aimed to determine the levels of both PGE(2) and Cyst-LTs in sputum supernatants of patients with asthma and to investigate the effect of smoking habit as well as their associations with inflammatory cells, bronchial hyperresponsiveness (BHR) and lung function. METHODS: Ninety-eight patients to asthma (47 smokers) and 40 healthy subjects (20 smokers) were studied. All subjects underwent sputum induction for cell count identification, PGE(2) and Cyst-LTs levels measurement in supernatants, pulmonary function tests and BHR to methacholine. RESULTS: Patients with asthma had significantly higher levels of both Cyst-LTs and PGE(2) in sputum supernatants compared to healthy subjects [median (interquartile ranges) 432 (287, 575) vs. 91.5 (73.5, 111) pg/mL and 654 (456,789) vs. 117.5 (92,157) pg/mL, respectively, P < 0.001 for both comparisons]. Smoking asthmatics had significantly higher Cyst-LTs and PGE(2) levels compared to non-smoking asthmatics. Cyst-LTs levels in sputum supernatant of smoking asthmatics presented a significant positive association with sputum eosinophils, while PGE(2) levels were positively associated with sputum neutrophils. CONCLUSIONS: The increased concentrations of PGE(2) and Cyst-LTs in sputum supernatants of smoking asthma are consistent with an up-regulation of these two mediators in this specific phenotype of asthma. Furthermore, Cyst-LTs are associated with eosinophilic inflammation, while PGE(2) is associated with the presence of neutrophilic inflammation in smoking asthma.

Increased levels of angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma.

BACKGROUND: Airway and vascular remodeling may play a prominent role in the clinical severity of severe refractory asthma (SRA). Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin-2 (Ang-2) acts as its natural inhibitor. OBJECTIVE: We aimed to determine the levels of angiopoietins in sputum supernatants of patients with SRA and to investigate the possible associations with mediators and cells involved in both the inflammatory and the vascular remodeling processes. METHODS: Thirty-eight patients with SRA, 35 patients with moderate asthma, and 20 healthy subjects were studied. All participants underwent lung function tests, bronchial hyperresponsiveness assessment and sputum induction for cell count identification and Ang-1, Ang-2, VEGF, TGF-ß1, Cys-LTs, MMP-2, IL-13, ECP, and IL-8 measurement in supernatants. Airway vascular permeability (AVP) index was also assessed. RESULTS: Ang-1 (ng/ml) and Ang-2 (pg/ml) levels were significantly elevated in patients with SRA compared with patients with moderate asthma and control subjects [median, interquartile ranges: 30 (17-39) vs 7.5 (5-11) vs 4.7 (3.8-5.9) respectively, P < 0.001; and 506 (400-700) vs 190 (146-236) vs 96 (89-120) respectively, P < 0.001]. Regression analysis showed a significant positive association between Ang-2 and AVP index, MMP-2, Ang-1, and VEGF in SRA. A weak association was also observed between Ang-1 and sputum eosinophils% in SRA. CONCLUSION: Our results indicate that both angiopoietins levels are higher in SRA compared with moderate asthma and healthy subjects. In SRA, Ang-2 is associated with mediators involved in both the inflammatory and the vascular remodeling processes.

Exhaled breath condensate in asthma: from bench to bedside.

The need for non-invasive assessment of airway inflammation is imperative, since inflammatory airway diseases, such as asthma and COPD, are characterized by variation in their clinical presentation throughout their course. Exhaled breath condensate (EBC) collection represents a rather appealing method that can be used to conveniently and noninvasively collect a wide range of volatile and non-volatile molecules from the respiratory tract, without affecting airway function or inflammation. Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values. A large number of mediators of inflammation, oxidative and nitrosative stress, including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, prostanoids, nitrogen oxides, peptides and cytokines, have been studied in EBC. This review focuses mainly on the presentation of the above biomarkers in asthma as well as on the effect of various factors on their concentrations. Concentrations of such mediators have been shown to be related to the underlying asthma and its severity and to be modulated by therapeutic interventions. Despite the encouraging positive results up-to-date, the introduction of EBC in everyday clinical practice requires the work-out of some methodological pitfalls, the standardization of EBC collection, and finally the identification of a reliable biomarker which is reproducible, has normal values and provides information for the underlying inflammatory process and the response to treatment. So far none of the parameters studied in EBC fulfils the aforementioned requirements.

C-reactive protein and procalcitonin as predictors of survival and septic shock in ventilator-associated pneumonia.

We evaluated the performance of procalcitonin (PCT) and C-reactive protein (CRP) threshold values and kinetics as predictors of ventilator-associated pneumonia (VAP) survival and septic shock development. 45 adult patients with VAP were studied. Serum CRP and PCT levels and the Sequential Organ Failure Assessment (SOFA) score were measured on days 1, 4 and 7 (D1, D4, D7) of VAP and their variations between different days (kinetics) were calculated (DeltaPCT, DeltaCRP). A multivariate logistic regression model was constructed with either VAP 28-day survival or septic shock development as dependent variables, and PCT values, CRP values, kinetics, age, sex, SOFA and Acute Physiology and Chronic Health Evaluation (APACHE) II score as independent variables. No difference was found in CRP levels between survivors and nonsurvivors. Nonsurvivors had significantly higher PCT levels on D1 and D7. In the multivariate analysis, the only factors predicting VAP survival were DeltaPCT(7-1) (OR 7.23, 95% CI 0.008-0.468) and DeltaCRP(7-4) (OR 4.59, 95% CI 0.013-0.824). VAP patients who developed septic shock had significantly higher CRP levels on D1 and D7 and higher PCT levels on D1 and D4. The only factor predicting the development of septic shock was SOFA on D1 (OR 7.44, 95% CI 1.330-5.715). Neither PCT and CRP threshold values nor their kinetics can predict VAP survival or septic shock development.

Adenosine deaminase activity and its isoenzymes in the sputum of patients with pulmonary tuberculosis.

BACKGROUND: Adenosine deaminase (ADA) has been widely used for the diagnosis of tuberculous pleural effusion. Two isoenzymes have been described, ADA(1) and ADA(2). OBJECTIVE: To evaluate the diagnostic value of sputum ADA, ADA(1) and ADA(2) activity in pulmonary tuberculosis (TB). DESIGN: We measured total ADA, ADA(1) and ADA(2) activity in the sputum of 27 patients with pulmonary TB (11 had a negative Ziehl-Neelsen stain for acid-fast bacilli [AFB]). Nineteen patients with lung cancer were used as controls. RESULTS: Sputum total ADA activity was significantly higher in TB than in lung cancer patients (median 18 U/l [range 3-70] vs. 6 U/l [2-16]; P < 0.001). Sputum ADA(2) activity was significantly higher in TB compared to lung cancer patients (9 U/l [0-65] vs. 5 U/l [0-12]; P = 0.001). Sputum ADA(2) was significantly higher than ADA(1) in TB patients (P = 0.001). Sputum ADA and ADA(2) were higher in both AFB-positive and AFB-negative TB patients. Using a cut-off level of respectively 16 UI/l and 5UI/l for sputum total ADA and ADA(2), sensitivity and specificity were 55.6% and 100% for total ADA and 81.5% and 63.2% for ADA(2). CONCLUSION: Sputum total ADA and ADA(2) levels are elevated in patients with pulmonary TB. As they are elevated even in AFB-negative patients, they may assist in the early diagnosis of pulmonary TB.

Carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 (CYFRA 21-1) levels in induced sputum of lung cancer patients.

OBJECTIVES: The diagnosis of lung cancer is usually based on the histological and cytological examination of material obtained by bronchoscopy. Tumour markers in serum are of little use as a diagnostic tool for lung cancer. We hypothesized that induced sputum could be a suitable material for measuring tumour markers and, accordingly, attempted to evaluate the diagnostic value of such measurements in lung cancer. Induced sputum is minimally invasive and readily obtainable. MATERIAL AND METHODS: Fifty patients with lung cancer and 24 subjects with chronic obstructive pulmonary disease (COPD) were included in the study. CEA, NSE and CYFRA 21-1 levels in serum and induced sputum were measured by immunoradiometric assays. RESULTS: Serum and sputum CEA, serum and sputum NSE and serum CYFRA 21-1 did not differ significantly between lung cancer and COPD patients. Sputum CYFRA 21-1 was 7 times greater in the lung cancer group than in the COPD group. This finding was true in both small cell (SCLC) and non-small cell (NSCLC) lung cancer. The sensitivity, specificity, positive and negative predictive values were 86, 75, 88 and 72%, respectively. CONCLUSION: Of tumour markers in induced sputum, sputum CYFRA 21-1 offered the best predictive values, although not sufficiently satisfactory to suggest its routine use in lung cancer diagnosis.