Glycated Hemoglobin: a promising biomarker for predicting acute exacerbation and short-term mortality of chronic obstructive pulmonary disease

Tayal D., Jain P., Bhardwaj M., Sharma A.

COPD is a chronic respiratory disease characterized by systemic inflammation caused primarily by tobacco use, and it is associated with an increased susceptibility to respiratory infections, both viral and bacterial, which are responsible for acute COPD exacerbations (AECOPD). Diabetes mellitus is one of the most common co-morbidities in COPD patients. In our study, we attempted to detect previously undiagnosed diabetes in AECOPD patients who presented to our Institute. The study included 100 patients who had been diagnosed with AECOPD. Pearson's coefficient correlation analysis was used to assess the relationship between various parameters. The vast majority of patients belonged to Group 3. (diagnosed at the time of admission as having type II diabetes). HbA1c had a significant positive correlation with BMI, cholesterol, and TLC, but a negative correlation with SpO2. Using HbA1C, nearly two-thirds of the AECOPD were newly diagnosed with diabetes mellitus. Our findings suggest that diabetes is significantly underdiagnosed in COPD patients.

Agustí A., Celli B.R., Criner G.J., Halpin D., Anzueto A., Barnes P., Bourbeau J., Han M.K., Martinez F.J., Montes de Oca M., Mortimer K., Papi A., Pavord I., Roche N., Salvi S., et. al.

Lacasse Y., Casaburi R., Sliwinski P., Chaouat A., Fletcher E., Haidl P., Maltais F.

Background Long-term oxygen therapy (LTOT) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia. However, the best method of management of moderate hypoxaemia not qualifying for LTOT (including isolated nocturnal desaturation) is uncertain. We examined the effect of home oxygen (either LTOT or nocturnal oxygen therapy) on overall survival in patients with COPD and moderate hypoxaemia. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINHAL, and Web of Science from database inception to Jan 13, 2022, for parallel-group randomised trials of long-term or nocturnal oxygen in patients with COPD and moderate daytime hypoxaemia or isolated nocturnal desaturation, or both. Control groups received usual care or ambient air through sham concentrators (placebo) throughout the study period. The primary outcome of interest was 3-year mortality. Crossover trials and trials of oxygen in severe hypoxaemia were excluded. Two reviewers applied inclusion and exclusion criteria to titles and abstracts and screened the full-text articles and reference lists of relevant studies. Aggregate data were extracted manually in duplicate using structured data collection forms. Methodological quality was assessed using the Cochrane Risk of Bias tool. Random-effects meta-analysis was used to pool individual studies. We considered the minimal clinically important difference for home oxygen to be a relative risk reduction in mortality at 3-year follow-up of 30–40%. The meta-analysis is registered on PROSPERO, CRD42021225372. Findings We identified 2192 studies and screened 1447 after removal of duplicates, of which 161 were subjected to full-text screening, and six were identified as being eligible for inclusion. These six randomised trials were published between 1992 and 2020 and the quality of evidence was high. In the primary meta-analysis (five trials; 1002 patients), we found the effect of home oxygen in reducing 3-year mortality to be small or absent (relative risk 0·91 [95% CI 0·72–1·16]; τ2 = 0·00), hence the lower limit of the 95% CI did not meet the prespecified minimal clinically important difference. Interpretation The results of our meta-analysis suggest that home oxygen probably makes little or no difference to 3-year mortality in patients with COPD and moderate hypoxaemia. The data do not support the widespread use of home oxygen in this patient population. Funding None.

Nagata K., Horie T., Chohnabayashi N., Jinta T., Tsugitomi R., Shiraki A., Tokioka F., Kadowaki T., Watanabe A., Fukui M., Kitajima T., Sato S., Tsuda T., Kishimoto N., Kita H., et. al.

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

López-Pardo M.E., Candal-Pedreira C., Valdés-Cuadrado L., Represas-Represas C., Ruano-Ravina A., Pérez-Ríos M.

The rising trend in hospital admissions among patients with chronic obstructive pulmonary disease (COPD) is worrying, not only because of the increasing costs, but also because of the worsening quality of life. We aimed to identify the predictive factors of hospital admission, re-admission and mortality of COPD patients through using information exclusively registered in electronic clinical records.We conducted a population-based case-control study. All data were sourced from the different information systems comprising the Galician Health Service electronic record database. We included in the study patients diagnosed with COPD (code R95 in the medical record), ≥35 years old and with at least one spirometry performed ≤3 years prior inclusion. We fitted three logistic regression models, each one to ascertain the factors that influence the probability of admission, re-admission, and mortality, and calculated odds ratios (OR) with their 95% confidence intervals (95% CI).COPD patients were admitted due to respiratory causes a mean of 1.51 times across the period December 2016-December 2017, with 55% requiring re-admission in the next 90 days. The factor most closely associated with the re-admission profile was home oxygen therapy (OR 3.06 95% CI 2.42-3.87), followed by male gender (OR 2.01 95% CI 1.48-2.72), a CHA2D-VASc scale score >2 (OR 1.28 95% CI 1.16-1.42), and severity by clinical risk group stratification (OR 1.14 95% CI 1.04-1.26). Male sex (OR 1.47 CI 95% 1.04-2.09), having been readmitted ≥2 times (OR 1.34 CI 95% 1.11-1.61) and being ≥70 years old (OR 1.05 CI 95% 1.03-1.08) increase the probability of dying from COPD during the study period.These results confirm the complexity of management of COPD exacerbations, and indicate the need to establish strategies that would ensure continuity of care after hospital admission, with the aim of preventing re-admissions and death.

Andreas S., Röver C., Heinz J., Taube C., Friede T.

A decreasing trend in exacerbation rates has been observed in COPD. Because mortality is linked to exacerbations, it is of interest to investigate whether a similar time trend is also present in mortality rates.We performed a systematic review of placebo groups in published randomised controlled trials. Mortality rate was modelled based on a Poisson distribution for the event counts. Adding information on mortality as well as on newly published studies on a previous database, we performed a meta-regression.Among the 56 included studies representing 14 166 patients, an annual decrease in mortality rates of 6.1% (−0.6%, 12.6%) (p=0.073) was observed. Consistent results were obtained in subgroups as well as when adjusting for potential confounders. The correlation between exacerbation rate and mortality rate was positive but weak as well as insignificant.In summary, analysis of randomised controlled trials in COPD patients showed a decrease in mortality in the placebo arms over the last two decades. This effect is comparable to the previously observed decrease in annual exacerbation rate. Albeit insignificant, our results suggest that care is needed in the design of new trials or when comparing results from trials published many years apart.

MacLeod M., Papi A., Contoli M., Beghé B., Celli B.R., Wedzicha J.A., Fabbri L.M.

In chronic obstructive pulmonary disease (COPD), exacerbations (ECOPD), characterized by an acute deterioration in respiratory symptoms, are fundamental events impacting negatively upon disease progression, comorbidities, wellbeing and mortality. ECOPD also represent the largest component of the socioeconomic burden of COPD. ECOPDs are currently defined as acute worsening of respiratory symptoms that require additional therapy. Definitions that require worsening of dyspnoea and sputum volume/purulence assume that acute infections, especially respiratory viral infections, and/or exposure to pollutants are the main cause of ECOPD. But other factors may contribute to ECOPD, such as the exacerbation of other respiratory diseases and non-respiratory diseases (e.g., heart failure, thromboembolism). The complexity of worsening dyspnoea has suggested a need to improve the definition of ECOPD using objective measurements such as blood counts and C-reactive protein to improve accuracy of diagnosis and a personalized approach to management. There are three time points when we can intervene to improve outcomes: acutely, to attenuate the length and severity of an established exacerbation; in the aftermath, to prevent early recurrence and readmission, which are common, and in the long-term, establishing preventative measures that reduce the risk of future events. Acute management includes interventions such as corticosteroids or antibiotics and measures to support the respiratory system, including non-invasive ventilation (NIV). Current therapies are broad and better understanding of clinical phenotypes and biomarkers may help to establish a more tailored approach, for example in relation to antibiotic prescription. Other unmet needs include effective treatment for viruses, which commonly cause exacerbations. Preventing early recurrence and readmission to hospital is important and the benefits of interventions such as antibiotics or anti-inflammatories in this period are not established. Domiciliary NIV in those patients who are persistently hypercapnic following discharge and pulmonary rehabilitation can have a positive impact. For long-term prevention, inhaled therapy is key. Dual bronchodilators reduce exacerbation frequency but in patients with continuing exacerbations, triple therapy should be considered, especially if blood eosinophils are elevated. Other options include phosphodiesterase inhibitors and macrolide antibiotics. ECOPD are a key component of the assessment of COPD severity and future outcomes (quality of life, hospitalisations, health care resource utilization, mortality) and are a central component in pharmacological management decisions. Targeted therapies directed towards specific pathways of inflammation are being explored in exacerbation prevention, and this is a promising avenue for future research.

Papathanassiou E., Papaioannou A.I., Papanikolaou I., Antonakis E., Makou I., Hillas G., Mizi E., Bakakos P., Apollonatou V., Verykokou G., Roussakis N., Tsilogianni Z., Papiris S., Loukides S.

Babel R.A., Dandekar M.P.

: Modern lifestyle, changing eating habits and reduced physical work have been known to culminate into making diabetes a global pandemic. Hyperglycemia during the course of diabetes is an important causative factor for the development of both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, stroke and peripheral artery disease) complications. In this article, we summarize several mechanisms accountable for the development of both microvascular and macrovascular complications of diabetes. Several metabolic and cellular events are linked to the augmentation of oxidative stress like the activation of advanced glycation end products (AGE) pathway, polyol pathway, Protein Kinase C (PKC) pathway, Poly-ADP Ribose Polymerase (PARP) and hexosamine pathway. Oxidative stress also leads to the production of reactive oxygen species (ROS) like hydroxyl radical, superoxide anion and peroxides. Enhanced levels of ROS rescind the anti-oxidant defence mechanisms associated with superoxide dismutase, glutathione and ascorbic acid. Moreover, ROS triggers oxidative damages at the level of DNA, protein and lipids, which eventually cause cell necrosis or apoptosis. These physiological insults may be related to the microvascular complications of diabetes by negatively impacting the eyes, kidneys and the brain. While underlying pathomechanism of the macrovascular complications is quite complex, hyperglycemia associated atherosclerotic abnormalities like changes in the coagulation system, thrombin formation, fibrinolysis, platelet and endothelial function and vascular smooth muscle are well proven. Since hyperglycemia also modulates the vascular inflammation, cytokines, macrophage activation and gene expression of growth factors, elevated blood glucose level may play a central role in the development of macrovascular complications of diabetes. Taken collectively, chronic hyperglycemia and increased production of ROS are the miscreants for the development of microvascular and macrovascular complications of diabetes.

Tsalamandris S., Antonopoulos A.S., Oikonomou E., Papamikroulis G., Vogiatzi G., Papaioannou S., Deftereos S., Tousoulis D.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.

Viniol C., Vogelmeier C.F.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. While COPD is a mainly chronic disease, a substantial number of patients suffer from exacerbations. Severe exacerbations are related to a significantly worse survival outcome. This review summarises the current knowledge on the different aspects of COPD exacerbations. The impact of risk factors and triggers such as smoking, severe airflow limitation, bronchiectasis, bacterial and viral infections and comorbidities is discussed. More severe exacerbations should be treated with β-agonists and anticholinergics as well as systemic corticosteroids. Antibiotic therapy should only be given to patients with presumed bacterial infection. Noninvasive ventilation is indicated in patients with respiratory failure. Smoking cessation is key to prevent further COPD exacerbations. Other aspects include choice of pharmacotherapy, including bronchodilators, inhaled corticosteroids, phosphodiesterase-4 inhibitors, long-term antibiotics and mucolytics. Better education and self-management as well as increased physical activity are important. Influenza and pneumococcal vaccination is recommended. Treatment of hypoxaemia and hypercapnia reduce the rate of COPD exacerbations, while most interventional bronchoscopic therapies increase exacerbation risk within the first months after the procedure.

Bishwakarma R., Zhang W., Lin Y., Kuo Y., Cardenas V.J., Sharma G.

Chronic obstructive pulmonary disease (COPD) is associated with persistent systemic inflammation. Anti-inflammatory therapies have been shown to decrease acute exacerbations of COPD. The antidiabetic medication metformin decreases oxidative stress and inflammation and may benefit patients with COPD. We aimed at investigating the effect of metformin on health care utilizations in patients with coexisting COPD and diabetes mellitus (DM).We studied 5% Medicare beneficiaries with coexisting COPD and DM prescribed metformin or other antidiabetics during the period 2007-2010. The primary outcome was COPD-specific emergency room (ER) visits and hospitalizations; the secondary outcome was all-cause ER visits and hospitalizations over the 2-year follow-up after the index antidiabetic prescription. The effects of metformin were examined by COPD complexity and compared with the effects of other antidiabetic medications.Among 11,260 patients, 3,193 were metformin users and 8,067 were nonusers. Metformin users were younger, were less sick, were less likely to be on oxygen, and had fewer hospitalizations in the prior year compared with the nonusers. Over a 2-year period, metformin users had lower COPD-specific and all-cause ER visits and hospitalizations (7.11% vs 9.61%, p

Sant’Anna T., Donária L., Hernandes N.A., Furlanetto K.C., Barbosa D.S., Gosselink R., Pitta F.

To analyze the relationship between oxygen desaturation episodes during a laboratory-based ADL protocol and in real-life routine in patients with stable chronic obstructive pulmonary disease (COPD). Twenty patients with stable COPD (12 men, 70 ± 7 years, FEV1% 54 ± 15 predicted) with no indication for long-term oxygen therapy (LTOT) were submitted to assessments including ADL performance by the Londrina ADL Protocol (LAP) and level of physical activity in daily life, both while submitted to simultaneous activity and pulse oximeter monitoring. Episodes of desaturation ≥ 4% (ED ≥ 4%) during the LAP were correlated both with ED ≥ 4% in daily life (r = 0.45) and number of episodes of SpO2 under 88% (ED < 88%) in daily life (r = 0.59). ED < 88% during the LAP was also correlated with ED < 88% in daily life (r = 0.51), explaining 43% of its variance. In stable patients with COPD and no indication of LTOT, episodes of desaturation during a lab-based ADL protocol are moderately related to episodes of desaturation in daily (real) life, especially those episodes under 88%.

Yang C., Liao W., Wang J., Tsai C., Lee J., Peng G., Lee C., Hsu C., Tsai S.

Acute hyperglycemia is a common condition among patients with diabetes who are admitted to the emergency department (ED) for acute ischemic stroke (AIS). Previous findings regarding the association between hyperglycemia at admission and adverse outcomes among patients with diabetes and AIS have been inconsistent. When investigating this association, it is necessary to consider premorbid blood glucose control. The objective of the current study was to assess whether HbA1c-based adjusted glycemic variables were associated with unfavorable outcomes among patients admitted to the hospital for AIS. We retrospectively analyzed data from 309 patients who were hospitalized for AIS at a single medical center in Taiwan between January 1, 2013, and October 31, 2015. We found that 1) HbA1c-based adjusted glycemic variables, including the glycemic gap and stress hyperglycemia ratio, were associated with both AIS severity and neurological status at discharge; additionally, 2) HbA1c-based adjusted glycemic variables showed superior discriminative power compared with acute hyperglycemia regarding the development of severe AIS. We conclude that both the glycemic gap and stress hyperglycemia ratio might be useful in assessing the disease severity and prognosis of patients presenting with AIS. Further prospective long-term follow-up studies should be performed to validate these findings.

Yang C., Liao W., Tang Z., Wang J., Lee C., Chang W., Hsu C., Tang S., Tsai S.

Acute hyperglycemia is a common finding in patients presenting to emergency departments (EDs) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Several studies have argued against the association between hyperglycemia at admission and adverse outcomes in patients with diabetes and an acute illness. Recent studies have shown that glucose-related variables (eg, glycemic gaps and stress hyperglycemia ratios) that are adjusted for glycated hemoglobin levels can indicate the severity of a variety of diseases. The objective of this study was to assess whether these hemoglobin A1c (HbA1c)-based adjusted average glycemic variables were associated with unfavorable outcomes in patients admitted to a hospital with AECOPD. We found that 1) pulmonary infection is a major risk factor for AECOPD; 2) a higher glycemic gap and modified stress hyperglycemia ratio were associated with the development of acute respiratory failure (ARF) in patients with diabetes admitted to an ED because of AECOPD; and 3) the glycemic gap and modified stress hyperglycemia ratio had superior discriminative power over acute hyperglycemia and HbA1c for predicting the development of ARF, although the HbA1c-adjusted glycemic variables alone were not independent risk factors for ARF.