Plasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD

doi:10.1378/chest.08-0047

Chest

Volume 134, Issue 2, August 2008, Pages 263-272

https://doi.org/10.1378/chest.08-0047 Get rights and content

Background

Plasma endothelin and adrenomedullin are increased in patients with pulmonary arterial hypertension, hypoxia, and pulmonary infections, conditions that predict survival in patients with COPD. We investigated whether plasma pro-endothelin-1 (proET-1) and/or pro-adrenomedullin (proADM) on admission to the hospital for acute exacerbation predict survival in patients with COPD.

Methods

We examined 167 patients who had been admitted to the hospital for acute exacerbation, and we followed them up for 2 years. We measured plasma C-terminal (CT) proET-1 and mid-regional (MR) proADM on hospital admission, after 14 to 18 days, and after 6 months. In addition to plasma CT proET-1 and MR proADM, we assessed with Cox regression univariate and multivariate analyses the predictive value of clinical, functional, and laboratory parameters on 2-year survival. We analyzed the time to death by Kaplan-Meier curves.

Results

Compared to recovery and stable state, CT-proET-1 and MR-proADM were significantly increased on hospital admission (p < 0.001 and p = 0.002, respectively). MR-proADM, but not CT-proET-1, was associated with increased in-hospital mortality (p = 0.049) and independently predicted 2-year survival (p = 0.017). ProADM plasma levels > 0.84 nmol/L on hospital admission increased the mortality risk within 2 years from 13 to 32% (p = 0.004). By contrast, age (p = 0.779), Charlson comorbidity score (p = 0.971), body mass index (p = 0.802), FEV₁ percent predicted (p = 0.741), PAo₂ (p = 0.744), PAco₂ (p = 0.284), leukocyte counts (p = 0.333), C-reactive protein (p = 0.772), procalcitonin (p = 0.069), pulmonary arterial hypertension (p = 0.971), and CT-proET-1 (p = 0.223) were not independently associated with 2-year survival.

Conclusions

This study shows that plasma proADM but not plasma proET-1 on admission to the hospital for acute exacerbation independently predicts survival, thus suggesting that this biomarker could be used to predict prognosis in patients with COPD.

Section snippets

Setting and Study Population

This prospective cohort study took advantage of baseline data from 167 patients with acute exacerbations of COPD, who were admitted to the emergency department of the University Hospital Basel and were included in a prospective, randomized trial.⁸ A predefined secondary end point was the assessment of further biomarkers in COPD patients.38, 39

The diagnosis of COPD was based on clinical history, physical examination findings, and spirometric criteria according to the Global Initiative for

Results

The detailed baseline characteristics of the 167 patients are presented in Table 1. Overall, 116 patients (69.5%) had relevant comorbidities. Sputum cultures grew bacterial pathogens in 65 cases (38.9%). Echocardiography results were available for 123 patients (73.7%). A total of 38 patients (22.8.%) demonstrated clinically relevant pulmonary arterial hypertension.⁴⁵ In 12 cases (7.2%), echocardiography showed decreased left ventricular ejection fraction (ejection fraction, ≤ 40%).

The median

Discussion

In this investigation, we have examined the predictive value of plasma proET-1 and proADM levels on survival in patients with acute exacerbations of COPD requiring hospitalization. We have reported three major findings. First, proET-1 and proADM levels were markedly increased at exacerbation and decreased significantly in the recovery and stable phases of the disease. Second, neither proET-1 nor proADM levels correlated consistently with the clinical presentation on hospital admission. Finally,

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Midregional proadrenomedullin safely reduces hospitalization in a low severity cohort with infections in the ED: a randomized controlled multi-centre interventional pilot study
2021, European Journal of Internal Medicine
The midregional fragment of proadrenomedullin (MR-proADM) is known to provide accurate short-, mid- and long term prognostic information in the triage and multi-dimensional risk assessment of patients in the emergency department (ED). In two independent observational cohorts MR-proADM values identified low disease severity patients without risk of disease progression in the ED with no 28 days mortality that wouldn´t require hospitalization. In this interventional study we want to show that the combination of an MR-proADM algorithm with clinical assessment is able to identify low risk patients not requiring hospitalization to safely reduce the number of hospital admissions.
A randomized-controlled interventional multicenter study in 4 EDs in Spain. The study protocol was approved by Ethics Committees. Control arm patients received Standard Care. MR-proADM guided arm patients with low MR-proADM value (≤0.87 nmol/L) were treated as out-patients, with high MR-proADM value (>0.87 nmol/L) were hospitalized. The hospitalization rate was compared between the study arms.
Two hundred patients with suspicion of infection were enrolled. In the MR-proADM guided arm the hospital admission rate in the intention-to-treat (ITT) population was 17% lower than in the control arm (40.6% vs. 57.6%, p=0.024) and 20% lower in the per protocol (PP) population (37.2% vs. 57.6%, p=0.009). No deaths of out-patients and no significant difference for the safety endpoints readmission and representation rates were observed. The readmission rate was only slightly higher in the MR-proADM guided arm compared to the control arm (PP population: at 14 days 9.3% vs. 7.1%, difference 2.1% (95% CI: -11.0% to 15.2%); and at 28 days 11.1% vs. 9.5%, difference 1.6% (95% CI: -12.2% to 15.4%)). The rate of 28 days representation was slightly lower in the MR-proADM guided arm compared to the control arm (20.4% vs. 26.2%, difference -5.8% (95% CI: -25.0% to 13.4%); PP population).
Implementing a MR-proADM algorithm optimizes ED workflows efficiently and sustainably. Hospitals can highly benefit from a reduced rate of hospitalizations by 20% using MR-proADM. The safety in the MR-proADM guided study arm was similar to the Standard Care arm.
ClinicalTrials.gov Identifier NCT03770533
Adrenomedullin mediates pro-angiogenic and pro-inflammatory cytokines in asthma and COPD
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Citation Excerpt :
In COPD, circulating pro-AM has been shown to predict clinical outcomes and survival [29,36]. Plasma pro-AM on admission to the hospital for acute exacerbation of COPD, independently predicts survival as it has been shown that pro-AM plasma levels, greater than 0.84 nmol/l on hospital admission, increased the mortality risk within 2 years from 13 to 32% [37]. Consequently, increased pro-AM levels in COPD may reflect disease severity including airway obstruction, as well as an overall cardiopulmonary distress.
Adrenomedullin (AM) is a pluripotent peptide hormone with contradictory effects in human health and disease. In chronic inflammatory lung diseases, such as asthma and COPD, AM has been shown to inhibit inflammation and cell proliferation. In the present study, we aimed to investigate the effect of AM on pro-angiogenic and pro-inflammatory cytokines in asthma and COPD.
Serum levels of pro-AM were measured in patients with asthma, COPD and matched controls. The effect of AM on intracellular signaling proteins and cytokine secretion was assessed in primary cultures of epithelial cells (EC) and airway smooth muscle cells (ASMC) established from endo-bronchial biopsies of patients with asthma, COPD and controls.
Serum pro-AM was higher in patients with asthma and COPD, compared to controls. AM stimulated cAMP in ASMC but not in EC. In EC, AM decreased Erk1/2 MAPK expression and activation but in ASMC, AM activated Erk1/2. This effect was similar in asthma, COPD and controls. AM stimulated the secretion of pro-angiogenic CXCL1 by EC of controls and CXCL5 by EC of asthma patients. AM did not affect the secretion of IL-6 or IL-8 by EC but stimulated the secretion of IL-6 by ASMC. In EC, AM inhibited the stimulatory effect of TGF-β and IL-4 on the secretion of IL-6 and IL-8 but had an additive stimulatory effect with TGF-β in ASMC.
These data suggest that AM mediates the secretion of pro-angiogenic and pro-inflammatory cytokines in a cell-type and/or a disease-specific way, explaining its association with clinical outcomes in COPD.
Stable-State Midrange Proadrenomedullin Is Associated With Severe Exacerbations in COPD
2018, Chest
Elevated levels of midrange proadrenomedullin (MR-proADM) are associated with worse outcome in different diseases, including COPD. The association of stable-state MR-proADM with severe acute exacerbations of COPD (AECOPDs) requiring hospitalization, or with community-acquired pneumonia (CAP) in patients with COPD, has not been studied yet. The aim of this study was to evaluate the association of stable-state MR-proADM with severe AECOPD and CAP in patients with COPD.
This study pooled data of 1,285 patients from the Cohort of Mortality and Inflammation in COPD (COMIC) and PRedicting Outcome using systemic Markers In Severe Exacerbations of Chronic Obstructive Pulmonary Disease (PROMISE-COPD) cohort studies. Time until first severe AECOPD was compared between patients with high (≥ 0.87 nmol/L) or low (< 0.87 nmol/L) levels of plasma MR-proADM in stable state as previously defined. For time until first CAP, only COMIC data (n = 795) were available.
Patients with COPD with high-level stable-state MR-proADM have a significantly higher risk for severe AECOPD compared with those with low-level MR-proADM with a corrected hazard ratio (HR) of 1.30 (95% CI, 1.01-1.68). Patients with high-level stable-state MR-proADM had a significantly higher risk for CAP compared with patients with COPD with low-level MR-proADM in univariate analysis (HR, 1.93; 95% CI, 1.24-3.01), but after correction for age, lung function, and previous AECOPD, the association was no longer significant (corrected HR, 1.10; 95% CI, 0.68-1.80).
Stable-state high-level MR-proADM in patients with COPD is associated with severe AECOPD but not with CAP.
What is the place for biomarkers during acute COPD exacerbations?
2017, Revue des Maladies Respiratoires
Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels
2016, American Journal of Transplantation
Citation Excerpt :
Interestingly, proADM at 72 h had better predictive utility for ICU mortality than grade 3 PGD at 72 h, and predictive utility was considerably increased by the combined use of the two items, although the difference did not reach statistical significance. Furthermore, we found that time on the ventilator and time in the ICU were longer in LT recipients with high levels of proADM measured at 72 h. Substantial evidence already exists regarding the value of proADM as a mortality predictor in patients with sepsis (15, in patients presenting at the emergency department with dyspnea (16, in patients with community-acquired pneumonia (17) and in those with chronic obstructive pulmonary disease (18). Shah et al demonstrated that the addition of biomarkers of epithelial injury and cell adhesion to clinical PGD grade added significant predictive value compared with PGD grade alone for 90-day mortality, with an AUC of 0.76 (95% CI 0.65–0.87) (4).
Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty-two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47–38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53–0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65–0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality.
Blood eosinophil count and GOLD stage predict response to maintenance azithromycin treatment in COPD patients with frequent exacerbations
2019, Respiratory Medicine
Maintenance treatment with macrolides are useful in preventing COPD exacerbations. We investigated which characteristics of COPD patients with frequent exacerbations predicted the best response to maintenance treatment with azithromycin.
This study was part of the COLUMBUS trial, a prospective randomized, double-blind, placebo-controlled study in 92 COPD patients with frequent exacerbations. During the 1-year treatment period, follow-up data were collected for spirometry, mMRC scores, sputum cultures and blood inflammatory markers.
In the azithromycin group a significant lower number of exacerbations per patient was observed in patients with the following characteristics: baseline blood eosinophil count ≥2.0% (x̄ = 1.26), compared to an eosinophil count < 2.0% (x̄ = 2.50; p = 0.02), GOLD stage 1–2 (x̄ = 1.06), versus GOLD stage 4 (x̄ = 2.62; p = 0.02) and GOLD group C (x̄ = 0.45) compared to group D (x̄ = 2.18; p < 0.01). Moreover, the number of hospitalizations was significantly lower in patients, with a blood eosinophil count ≥2.0% (x̄ = 0.26) compared to an eosinophil count < 2.0% (x̄ = 0.90; p = 0.01) and in GOLD stages 1–2 (x̄ = 1.06) compared to stage 4 (x̄ = 2.62; p = 0.04).
In conclusion, azithromycin maintenance treatment appears to be effective in COPD patients with frequent exacerbations, who are either classified in GOLD stage 1–2 or GOLD C and those with a blood eosinophil count of ≥2.0%.

View all citing articles on Scopus

: Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

¹: Dr. Stolz was partially supported by grants from the Swiss National Foundation and the Margarete and Walter Lichtenstein Foundation.

²: Dr. Stolz has received speakers' honoraria from BRAHMS AG (the manufacturer of proADM, pro-endothelin, and procalcitonin assays).

³: Drs. Müller, Müller, and Christ-Crain served as consultants and were sponsored by BRAHMS AG for attending advisory board meetings, speaking engagements, and research.

⁴: Drs. Morgenthaler and Struck are employees of BRAHMS AG.

⁵: Drs. Christ-Cain, Miedinger, Leuppi, Bingisser, and Tamm have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Chest

Original ResearchCOPDPlasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD

Background

Methods

Results

Conclusions

Section snippets

Setting and Study Population

Results

Discussion

Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data

Lancet

Deaths: preliminary data for 2003

Natl Vital Stat Rep

Quality of care for patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease

Ann Intern Med

Exacerbations of chronic obstructive pulmonary disease

Eur Respir J

Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD

Chest

Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease

Thorax

Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy

Chest

C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease

Am J Respir Crit Care Med

C-reactive protein levels and clinically important predictive outcomes in stable COPD patients

Eur Respir J

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease

Thorax

Pulmonary biomarkers in chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease

Thorax

The impact of COPD on hospital resources: the specific burden of COPD patients with high rates of hospitalization

Arch Bronconeumol

Pharmacoeconomic evaluation of COPD

Chest

Prognostic factors in chronic obstructive pulmonary disease

Arch Bronconeumol

Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow

Circulation

Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?

Ann Intern Med

Endothelial cell responses to hypoxic stress

Clin Exp Pharmacol Physiol

Distribution of immunoreactive endothelin in the lungs of mice during respiratory viral infection

Eur Respir J

Endothelin-mediated increases in lung VEGF content promote vascular leak in young rats exposed to viral infection and hypoxia

Am J Physiol Lung Cell Mol Physiol

Endothelin-1 induces GM-CSF, IL-6 and IL-8 but not G-CSF release from a human bronchial epithelial cell line (BEAS-2B)

Neuropeptides

Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue

Endocrinology

Plasma levels of adrenomedullin in primary and secondary pulmonary hypertension in patients < 20 years of age

Am J Cardiol

Increased adrenomedullin expression in lungs in endotoxaemia

J Endocrinol

Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners

J Biol Chem

Identification of an adrenomedullin precursor fragment in plasma of sepsis patients

Peptides

Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma

Clin Chem

Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome

Am J Respir Crit Care Med

Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction

J Am Coll Cardiol

Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study

J Am Coll Cardiol

Long-term prognostic value of midregional pro-adrenomedullin and C-terminal pro-endothelin-1 in patients with acute myocardial infarction

Clin Chem Lab Med

Original Research
COPD
Plasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD