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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 2-22

Cardiac troponin I – A prognostic marker in acute exacerbation of chronic obstructive pulmonary disease


Department of Respiratory Medicine, Apollo Main Hospital, Chennai, Tamil Nadu, India

Date of Submission03-Jun-2021
Date of Decision14-Jul-2021
Date of Acceptance20-Jul-2021
Date of Web Publication22-Sep-2021

Correspondence Address:
P Amal Johnson
Associate Consultant Pulmonologist, Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, TamilNadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/japt.japt_25_21

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  Abstract 


Aim: The aim of this study is to assess the use of cardiac troponin I as a prognostic marker in the acute exacerbation of COPD. Objectives: Primary Objective: Evaluate the prevalence of elevation of cTnI in patients admitted with acute exacerbation of COPD. Secondary Objective: Evaluate the association of longer duration of COPD, lower SpO2 and higher PaCO2 at admission, increased need for ventilatory support, increased duration of hospital stay and increased inhospital mortality in cTnI positive patients. Material And Methods: Study Site: Apollo Main Hospital, Chennai Study Population: Patients greater than 40 years with spirometry confirmed COPD according to GOLD guidelines admitted with AECOPD in the emergency or ward in the specified period. Study Design: Prospective, Observational Study Sample Size With Justification: 62 cases. Study Duration: From JANUARY 2018 to NOVEMBER 2019. Inclusion Criteria: Study to be conducted in 62 patients with Spirometry confirmed COPD according to GOLD guidelines, age greater than 40 years and admitted with AECOPD in the emergency or ward in the specified period. Exclusion Criteria: Patients with the below mentioned are all excluded from the study - Acute coronary syndrome, post CPR. post cardiac surgery, persistent hemodynamic instability, acute aortic dissection, pulmonary embolism, primary lung diseases other than COPD, patient already on NIV, marked renal failure, severe anaemia, sepsis ,stroke. Study Methodology: The study design is prospective, observational and non-interventional. Study to be conducted in patients with spirometry proven COPD according to GOLD guidelines admitted with AECOPD in the emergency, ward, HDU, MDCCU in the specified period. Detailed medical history along with smoking history, comorbidities and medication history noted, general and respiratory examination to be done for every patient at the time of admission.SpO2 under room air, O2 requirement, ABG values, CXR, Hemogram values, creatinine levels, ECG findings, ECHO findings at the time of admission to be noted. Blood sample to be taken to analyse serum cTnI levels along with routine investigations with informed consent from each patient at initial point of care. Cardiac Troponin I to be estimated by immunochromatographic qualitative assay, DIAQUICK Troponin I cassette. The DIAQUICK Troponin I Cassette is an immunochromatographic assay. The minimum detection level is 1.0 ng/ml with Sensitivity 95%, Specificity 97% and Accuracy 90%. Whether the patient was admitted in ward or ICU, whether the patient required any ventilatory support (NIV or invasive ventilation), duration of the stay in the hospital was all followed up. The end point of the follow up is discharge or death. Results: Out of the 62 patients, 7(11.3%) patients were tested to be Troponin I positive during exacerbation. These patients had longer duration of COPD, increased presence of Pulmonary hypertension, Lower Spo2 on room air and higher PaCo2 at presentation, increased requirement of ventilatory support with ICU care and more duration of hospitalization.

Keywords: Chronic obstructive pulmonary disease, exacerbation, troponin


How to cite this article:
Johnson P A, Narasimhan R. Cardiac troponin I – A prognostic marker in acute exacerbation of chronic obstructive pulmonary disease. J Assoc Pulmonologist Tamilnadu 2021;4:2-22

How to cite this URL:
Johnson P A, Narasimhan R. Cardiac troponin I – A prognostic marker in acute exacerbation of chronic obstructive pulmonary disease. J Assoc Pulmonologist Tamilnadu [serial online] 2021 [cited 2022 Jan 28];4:2-22. Available from: http://www.japt.com/text.asp?2021/4/1/2/326411




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death and the twelfth leading cause of disability worldwide and is expected to climb to 3rd and 5th, respectively, in 2020.[1] Acute exacerbation of COPD (AECOPD) is associated with worsening of lung function and increased risk of both in-hospital and long-term mortality. Cardiovascular disease is a major comorbidity and the cause of >one-third of mortality.[2]

Troponins (Tns) are regulatory protein complex that participates in muscle contraction between myosin and actin found in cardiac and skeletal muscles. There are three different protein components – T, I, and C. Tns are released in blood when there is a break in the muscle cell membrane integrity. Human cardiac TnI (cTnI) has additional amino acid residues on its N-terminal end, which do not exist on the skeletal forms, thus making cTnI specific for myocardial injury.[3],[4]

Studies done in assessing the role of TnT and TnI in diagnosis of acute myocardial injury showed that both have excellent diagnostic accuracy with TnI slightly better compared with TnT.[5] Modern assays can detect cTnI as early as 4–6 h after onset of myocardial damage, and its levels remain elevated for up to 6–10 days. There are several other conditions that can also cause elevation of cTnI, apart from acute coronary syndrome. They are cardiac trauma, after cardiopulmonary resuscitation cardiopulmonary resuscitation (CPR), acute aortic dissection, pulmonary embolism, AECOPD, postcardiac surgery, stroke, sepsis, renal failure, and severe anemia.[6]

There are very little data available addressing the association between cTnI and outcome in patients hospitalized for AECOPD.[7],[8] Studies done so far show that there is an elevation of cTnI in a significant subset of patients admitted with AECOPD and is associated with longer duration of COPD, lower SpO2 and high PaCO2 at admission, longer duration of admission, more likely to require intensive care unit (ICU) care, ventilatory support (both noninvasive and invasive), and higher rates of in-hospital mortality.[9]

The exact mechanism of cTnI elevation in AECOPD is not known. The proposed reasons are increased pressure in pulmonary circulation, leading to increased right ventricular (RV) overload, exacerbation of the preexisting heart failure, hypoxia, and tachycardia causing an imbalance between oxygen demand and delivery, and increased inflammatory markers causing a subclinical myocardial injury.[10]

This study prospectively analyzes the relationship between cTnI and outcome of patients admitted with AECOPD, thus assessing the utility of TnI as a prognostic marker in AECOPD.

Review of Literature

The review of literature is discussed under the following headings:

  1. COPD including AECOPD
  2. Cardiovascular comorbidity in COPD
  3. cTns
  4. Role of cTns in AECOPD.


Definition

COPD is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.[11]

Classification of severity of airflow limitation in chronic obstructive pulmonary disease

In pulmonary function testing, a postbronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of <0.70 is commonly considered diagnostic for COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) system categories airflow limitation into stages. In patients with FEV1/FVC <0.70:

  • GOLD 1 – Mild: FEV1 80% predicted
  • GOLD 2 – Moderate: 50% ≤FEV1 <80% predicted
  • GOLD 3 – Severe: 30% ≤FEV1 <50% predicted
  • GOLD 4 – Very severe: FEV1 <30% predicted.


The GOLD guideline uses a combined COPD assessment approach to group patients according to symptoms and previous history of exacerbations. Symptoms are assessed using the Modified British Medical Research Council (mMRC) or COPD assessment test (CAT) scale.

  • Group A: low-risk (0–1 exacerbation per year, not requiring hospitalization) and fewer symptoms (mMRC 0–1 or CAT <10)
  • Group B: low-risk (0–1 exacerbation per year, not requiring hospitalization) and more symptoms (mMRC ≥2 or CAT ≥10)
  • Group C: high-risk (≥2 exacerbations per year, or one or more requiring hospitalization) and fewer symptoms (mMRC 0–1 or CAT <10)
  • Group D: high-risk (≥2 exacerbations per year, or one or more requiring hospitalization) and more symptoms (mMRC ≥2 or CAT ≥10).[11]


Acute exacerbation of chronic obstructive pulmonary disease

An exacerbation of COPD is defined as an acute worsening of respiratory symptoms that results in additional therapy.[12],[13] Exacerbations of COPD are important events in the management of COPD because they negatively impact health status, rates of hospitalization and readmission, and disease progression. COPD exacerbations are complex events usually associated with increased airway inflammation, increased mucus production, and marked gas trapping. These changes contribute to increased dyspnea that is the key symptom of an exacerbation. Other symptoms include increased sputum purulence and volume, together with increased cough and wheeze.[14]

Exacerbations are triggered by respiratory infections with bacteria or viruses (which may coexist), environmental pollutants, or unknown factors often occur in patients with COPD; a characteristic response with increased inflammation occurs during episodes of bacterial or viral infection. During exacerbations, there is increased hyperinflation and gas trapping, with reduced expiratory flow, thus accounting for increased dyspnea.[15] There is also worsening of V/Q abnormalities that can result in hypoxemia.[16] During exacerbations, there is evidence of increased airway inflammation. Other conditions (pneumonia, thromboembolism, and acute cardiac failure) may mimic or aggravate an exacerbation of COPD.

Exacerbations are classified as:

  • Mild (treated with short-acting bronchodilators only, SABDs)
  • Moderate (treated with SABDs plus antibiotics and/or oral corticosteroids)
  • Severe (patient requires hospitalization or visits the emergency room). Severe exacerbations may also be associated with acute respiratory failure.[11]


During a COPD exacerbation, symptoms usually last between 7 and 10 days, but some events may last longer. At 8 weeks, 20% of patients have not recovered to their preexacerbation state.[17] It is well established that COPD exacerbations contribute to disease progression.[18] Disease progression is even more likely if recovery from exacerbations is slow.[19] Exacerbations can also cluster in time, and once a COPD patient experiences an exacerbation, they will show increased susceptibility to another event.[20],[21]

Comorbidity in chronic obstructive pulmonary disease

It is well recognized that COPD is more than a respiratory disease. Comorbidities, defined as the coexistence of other medical conditions alongside COPD, contribute to the severity of disease in individual patients.[22] Although not necessarily causally associated with the disease, the existence of COPD may actually increase the risk of other diseases.[23] Comorbidities can occur in patients with any degree of airflow limitation and are not restricted to patients with advanced COPD Moreover, comorbidities are associated with increased morbidity and mortality. The increased understanding of COPD as a systemic disease has important clinical implications. In addition to traditional pharmacological therapy focused on treating chronic airflow limitation, management of COPD now requires a more holistic approach, including the assessment and appropriate treatment of comorbid conditions. Pulmonary rehabilitation is a nonpharmacological intervention with potential benefits for patients with comorbid conditions.

Comorbidities commonly associated with COPD as follows: [24],[25]

  • Cardiovascular disease
  • Hypertension
  • Coronary artery disease
  • Systolic and/or diastolic left ventricular (LV) dysfunction
  • Pulmonary hypertension
  • Peripheral vascular disease
  • Cerebrovascular disease
  • Stroke
  • Skeletal muscle dysfunction and loss of muscle mass
  • Osteoporosis, osteopenia or osteoarthritis
  • Psychological disturbances
  • Depression
  • Anxiety
  • Cognitive impairment
  • Anemia
  • Obstructive sleep apnea
  • Diabetes/metabolic syndrome
  • Renal insufficiency
  • Gastroesophageal reflux disease
  • Lung cancer
  • Infectious disease.


Cardiovascular comorbidity in chronic obstructive pulmonary disease

Cardiovascular disease is a major comorbidity in patients with COPD and is associated with poorer outcomes in COPD exacerbations.[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] The link between COPD and CAD is independent of any other confounding coronary risk factors such as smoking, cholesterol, systemic hypertension, and body mass index (BMI).[37] Systemic inflammation increases during AECOPD, providing a potential mechanism to explain the increased risk of cardiovascular events associated with AECOPD. In coronary artery disease, the activation of immune cells in the atheromatous plaque induces the production of cytokines such as interferon gamma, interleukin-1 (IL-1), tumor necrosis factor (TNF-a), IL-6m, and acute-phase inflammatory proteins.[38] The same mediators are involved in the inflammatory reaction observed in the bronchus in COPD. In addition to these shared pathophysiological determinants, the presence of COPD could contribute to the development of cardiovascular disease through hypoxia, systemic inflammation, and oxidative stress[39] and through impaired vasodilatory capacity.[40]

In the Lung Health Study conducted by Anthonisen et al. published in 1994, 12.8% of the 58,887 smokers were hospitalized with 42% of the hospitalizations secondary to cardiovascular events.[2]

In the review by Holguin et al. published in 2005 entitled “Comorbidity and mortality in COPD–related hospitalization in United states from 1979 to 2001” over 4,700,000 discharges, comorbidities were frequently reported in hospitalized patients with primary or secondary COPD diagnoses: hypertension 17%, cardiac disease 25%, diabetes 11%, pneumonia 12%; all higher than in the control group.[41]

In a study of over 45,000 patients with COPD done by Sidney et al. published in Chest (2005), heart failure was the leading cause of hospitalization, followed by myocardial infarction (MI) and stroke.[42]

Curkendall et al. in 2006 published “Cardiovascular disease in patients with COPD, Saskatchewan Canada cardiovascular disease in COPD patients” in Annals of Epidemiology found that the prevalence of all cardiovascular diseases was higher in patients with COPD compared with control subjects and that the risk of hospitalization and mortality due to cardiovascular causes was also elevated in patients with COPD.[43]

In another study of 270 hospitalized patients with COPD published in 1997 in European Respiratory Journal entitled “Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease,” Antonelli Incalzi et al. noted hypertension in 28%, diabetes in 14%, and ischemic heart disease in 10%.[44]

Kinnunen et al. in their study with titled “Impact of comorbidities on the duration of COPD patients' hospital episodes” published in Respiratory Medical Journal (1997) found that comorbidities had an impact on the duration of COPD hospitalizations and reported a mean length of stay of 7.7 days without any comorbidity compared with 10.5 days if a concurrent disease was present.[45]

Cardiovascular disease was a much more common cause of death than due to COPD in patients with COPD (27.6% vs. 14.3%).[46]


  Cardiac Troponins Top


cTns are regulatory proteins that control the calcium-mediated interaction of actin and myosin. The Tn complex consists of three subunits: TnT, TnI, and TnC. The Tn complex is not found in smooth muscle. Differing isoforms of the Tn proteins are expressed in striated muscle as compared to skeletal muscle. cTnT varies from skeletal TnT by a unique set of amino acids, where cTnI differs from skeletal TnI by a significant difference in the sequence of 31 amino acids and is a more specific marker for cardiac injury.[47],[48],[49],[50],[51]

Tn is a marker of cardiac injury and is not specific to acute MI.

Non-MI causes of an elevated Tn are as follows:

  1. Tachycardia and arrhythmia[51]
  2. Hypertrophic cardiomyopathy,[52] aortic dissection,[53] and coronary vasospasm[54]
  3. Direct myocardial damage due to contusion, cardioversion, infiltration, toxins, and drugs[55],[56]
  4. Critically ill patients including sepsis[57],[58],[59],[60],[61]
  5. Acute neurological diseases such as stroke or subarachnoid hemorrhage[62],[63],[64],[65]
  6. Renal failure[66],[67],[68]
  7. Patients admitted with respiratory failure, pulmonary embolism, and AECOPD.[69]


Possible Pathophysiologic mechanisms for cardiac troponin I elevation in conditions other than MI are[70],[71],[72],[73],[74]

  • Demand ischemia is the mismatch between myocardial oxygen demand and supply. AHA refers to Type 2 MI when the event is secondary to ischemia due to either an increased oxygen demand or a decreased supply in the absence of an acute primary coronary thrombotic event. With prolonged ischemia, myocytes are irreversibly damaged. The cell membrane degrades followed by Tn release into the circulation
  • Myocardial stress
  • Inflammation
  • Infiltration into myocardium
  • Immunological mechanisms


The enzyme concentration peaks from the 2nd to 5th day remain elevated for 7 days allowing for the diagnosis of recent myocardial injury. The upper reference limit of cTn level is defined as the 97.5th percentile of the values measure in the normal control population. MI should be diagnosed if cTnI levels are higher than the 99th percentile with a coefficient of variation of 10% or less detected within 24 h after the index clinical event. Values in the intermediate zone suggest minor myocardial damage.[75],[76] cTnI-positive cutoff for myocardial necrosis/injury is 0.1 ug/l.[74]

Cardiac troponin in acute exacerbation of chronic obstructive pulmonary disease

Pizarro et al. in their study titled “Diagnostic and therapeutic implications of elevated plasma troponin in acute exacerbated chronic obstructive pulmonary disease” published in Pneumologie 2016 stated that elevated Tn has been detected up to 74% of patients with AECOPD.[77]

Steer et al. in their article titled “Predicting outcomes following hospitalization for acute exacerbations of COPD” published in QJM: An International Journal of Medicine in November 2010 stated that “elevated serum Tn may result not only from acute cardiac dysfunction during the hospital stay but also relates to ongoing cardiac comorbidity.” As cardiac disease is the most frequent cause of death in patients with COPD, elevated Tn independently predicts death following discharge.[78]

Hoiseth et al. in their prospective study “Elevated high sensitivity cardiac troponin T is associated with increased mortality after exacerbation of chronic obstructive pulmonary disease” published in Thorax in 2011 assessed the association of cTnT with posthospitalization mortality rate associated with COPD exacerbation. Eight hundred and ninety-seven patients discharged after treatment of COPD exacerbation in the period 2000–2003 were identified and followed up for 1.9 years. In 316 patients, cTnT values were available. Elevated cTnT was significantly associated with increased mortality in the observation period with the hazard ratio of 1.64.[79]

Søyseth et al. in their study entitled “Acute exacerbation of COPD is associated with fourfold elevation of cardiac troponin T” published in Heart in January 2013 showed that “AECOPD is associated with increased cTnT compared with stable COPD.”[80]

Catherina et al. in their study entitled “Biochemical markers of cardiac dysfunction predict mortality in acute exacerbation of COPD” published in Thorax in 2011 showed that elevated TnT was found in 16.6% of patients.[81]

Brekke et al. in their study “Determinants of cardiac troponin T elevation in COPD exacerbation – A cross-sectional study” published in BMC Pulmonary Medicine showed that out of the patients admitted with COPD exacerbation in between 2000 and 2003 in the center, 441 had measurement of cTnI performed and 120 patients (27%) had elevated cTnI levels.[82]

Leonardo et al. in their article entitled “Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines” published in Thorax in 2011 stated that “TnT was abnormal in significant number of patients hospitalized because of AECOPD.”[83]

Zhao et al. in their study entitled “Elevated cardiac troponin T in patients with COPD” published in the International Journal of Medical Sciences in 2013 stated that “the TnT levels were significantly elevated in AECOPD and also associated with the severity of the disease.”[10]

Chaudary et al. in their study entitled “Prognostic value of cardiac-specific troponins in chronic obstructive pulmonary disease exacerbations: A systematic review” published in Journal of Mississippi State Medical Association in 2014 reviewed the association between cardiac Tns and mortality in patients hospitalized for COPD exacerbations. Nine research reports (4 prospective, 5 retrospective) qualified for review. Mortality was consistently increased in seven of these studies among COPD patients who had elevated Tn levels during an exacerbation. The review shows a strong direct association between cTn and mortality in patients hospitalized for COPD exacerbations.[29]

Campo et al. did an observational study entitled “Relationship between troponin elevation, cardiovascular history and adverse events in patients with acute exacerbation of COPD” which was published in the Journal of Chronic Obstructive Pulmonary Disease. 935 patients were admitted to the hospital for AECOPD from January 2010 to December 2012, and 694 patients were included in the study. 484 (70%) patients had positive cTnT. All adverse events were significantly higher in positive TnT group as compared to negative TnT group. In conclusion, after hospital admission for AECOPD, there is a significant increase in the risk of cardiac adverse events in patients with TnT elevation.[84]

Odigie et al. in their study “COPD exacerbation and myocardial injury” published in American Journal of Respiratory and Critical Care Medicine in 2009 resulted that elevated Tn seen in 11% of patients with AECOPD.[85]

Jiang in their study entitled “Clinical significance of serum cardiac markers in patients of chronic obstructive of COPD with hypoxemia” published in China Journal of Modern Medicine in 2006 showed that hypoxia may significantly increase the level of serum cardiac markers (cTn) and it has a significantly negative relation to PaO2 level.[86]

Noorain in his study entitled, “Prognostic value of cardiac troponin I during acute exacerbation of chronic obstructive pulmonary disease: A prospective study” published in Lung India in 2016 concluded that cTnI is elevated in a significant subset of patients (38%) with AECOPD. Duration of their illness was longer; higher incidence of ischemic heart disease was also found in these patients. Patients with cTnI elevation are more likely to require ICU care and ventilator support. However, it did not predict in-hospital mortality. Thus, it can be used as a marker to identify high-risk patients during AECOPD.[9]

Baillard et al., in their study “Cardiac troponin I in patients with severe exacerbation of chronic obstructive pulmonary disease” published in Journal of Intensive Care Medicine in 2003, stated that “elevated cTnI is a strong and independent predictor of in hospital death in patients admitted for acutely exacerbated COPD.”[87]

Abdel et al. in their study entitled “Serum troponin-I as a prognostic marker in acute exacerbated chronic obstructive pulmonary disease patients” published in Egyptian Journal of Chest Diseases and Tuberculosis in 2013 showed that out of 60 patients admitted with AECOPD, cTnI was positive in 42 AECOPD patients. cTnI positivity was more prominent among patients with very severe exacerbation of COPD and in those with past history of Long term oxygen therapy (LTOT) Mechanical ventilation (MV) and ICU admission. Further, cTnI positivity was more in patients admitted to ICU.[88]

Marcun et al. in their study “Cardiac biomarkers predict outcome after hospitalization for an acute exacerbation of chronic obstructive pulmonary disease” published in International Journal of Cardiology in 2012 concluded that out of the 127 patients included with AECOPD in the study, 53 were admitted. TnI on admission predicted mortality with hazard ratio 2.89.[89]

Gupta et al. in their study done with a study population of 50 patients admitted in AECOPD entitled “Cardiac troponin I as mortality predictor in acute exacerbation of chronic obstructive pulmonary disease” published in International Journal of Respiratory Medical Sciences in 2017 concluded that “the serum cTnI was found to be positive in 34% of patients with AECOPD. The patients with cTn positive had significantly higher mean PaCO2 levels and higher requirement for invasive or noninvasive ventilation. cTnI may be considered as a biomarker to predict mortality in AECOPD patients.”[7]

Martins et al. in their study with 173 patients entitled “Prognostic value of cardiac troponin I in patients with COPD acute exacerbation” published in Netherland Journal of Medicine in 2009 concluded that “in patients hospitalized for acute COPD exacerbations, nearly 70% had positive cTnI, elevated cTnI were associated with a greater need for non-invasive ventilatory support and were significant predictors of 18-month overall survival.[90]

Harvey did the study entitled “Elevation of cardiac troponins in exacerbation of chronic obstructive pulmonary disease” published in Journal of Emergency Medicine of Australia in June 2004. The results of the study are “troponin elevation was observed in 58 of 235 (25%) presentations in which troponin was measured. Patients with raised troponins tended to be older (75.7 vs. 70.0 years, P = 0.001), had lower pulse oximetry (85.6% vs. 89.6%, P = 0.003), were more acidotic (pH 7.34 vs. 7.40, P = 0.002), and were more hypercapnic (pCO2 58.0 vs. 49.1, P = 0.04). There were no significant differences in serum creatine kinase. Patients with raised troponins had significantly longer admissions (5 vs. 3 days, P = 0.001). Serum troponins are commonly raised in AECOPD and appear to reflect the severity of the exacerbation.[91]

Abroug et al. in their study entitled “Association of left-heart dysfunction with severe exacerbation of chronic obstructive pulmonary disease: Diagnostic performance of cardiac biomarkers” published in the American Journal of Respiratory and Critical Care Medicine in 2006 showed that in 148 consecutive patients admitted in intensive care for AECOPD included for the study, TnI was elevated in statistically significant number of cases in AECOPD.[92]

Study entitled “Cardiac troponin-I predicts long-term mortality in chronic obstructive pulmonary disease” published in the Journal of Chronic Obstructive Pulmonary Disease in 2009 was done by Fruchter et al.; 182 patients with acute exacerbation in whom TnI levels were sampled during their hospitalization were reviewed retrospectively. TnI levels were significantly higher in nonsurvivors compared with survivors. Elevated TnI level measured in patients with COPD during acute exacerbation is a strong independent predictor of mortality following discharge.[93]

Marun et al. in their prospective study titled “Cardiac biomarkers predict outcome after hospitalization for an acute exacerbation of chronic obstructive pulmonary disease” conducted in 127 patients and published in Internal Journal of Cardiology (2012) concluded that TnT was elevated in 60% of patients on admission and associated with increased mortality.[94]

In the article published by Fefri Abrough et al. (2006) in American Journal of Respiratory and Critical Care Medicine entitled “Association of left heart dysfunction with severe exacerbation of chronic obstructive pulmonary disease,” TnT positivity was not associated with LV dysfunction in patients admitted with AECOPD in 55.4%.[95]

Youssef et al. published their study entitled “Serum troponin-I as a prognostic marker in acute exacerbated chronic obstructive pulmonary disease patients” in Egyptian Journal of Chest Diseases and Tuberculosis (2013). Sixty patients were included in the study and cTnI was positive in 42 patients (70%) and more prominent in patients with severe exacerbation.[93]


  Aim and Objectives Top


Aim

The aim of this study is to assess the use of cTnI as a prognostic marker in the AECOPD.

Objectives

Primary objective

To evaluate the prevalence of elevation of cTnI in patients admitted with AECOPD.

Secondary objective

To evaluate the association of longer duration of COPD, lower SpO2 and higher PaCO2 at admission, increased need for ventilatory support, increased duration of hospital stay, and increased in-hospital mortality in cTnI-positive patients.


  Materials and Methods Top


  • Study site: Apollo Main Hospital, Chennai
  • Study population: Patients >40 years with spirometry confirmed COPD according to the GOLD guidelines admitted with AECOPD in the emergency or ward in the specified period
  • Study design: Prospective, observational study
  • Sample size with justification: 62 cases


Since primary objective of the study is to evaluate the prevalence of elevation of Tn values in patients admitted to our hospital with AECOPD, we took 38%[9] as the percentage of patients having Tn values for the workup of sample size calculation. Using the following formula,

n2 = z2 pq/d2 where

z = Standard normal variate value = 1.96

p = Troponin positivity in AECOPD patients = 38%

q = 1 − P = 62%

d = Clinical allowable error = 12%

Therefore, the required sample cases are 62 cases.

  • Study duration: From January 2018 to November 2019.


Inclusion criteria

The study to be conducted in 62 patients with

  • Spirometry confirmed COPD according to the GOLD guidelines
  • Age >40 years
  • Admitted with AECOPD in the emergency or ward in the specified period.


Exclusion criteria

Patients with the below mentioned are all excluded from the study

  • Acute coronary syndrome
  • Post-CPR
  • Post-cardiac surgery
  • Persistent hemodynamic instability
  • Acute aortic dissection
  • Pulmonary embolism
  • Primary lung diseases other than COPD
  • Patient already on noninvasive ventilation (NIV)
  • Marked renal failure
  • Severe anemia
  • Sepsis
  • Stroke.


Study methodology

The study design is prospective, observational, and noninterventional. The study to be conducted in patients with spirometry-proven COPD according to the GOLD guidelines admitted with AECOPD in the emergency, ward, High dependency unit (HDU), and Multidisciplinary critical care unit (MDCCU) in the specified period. An exacerbation of COPD is defined as an acute worsening of respiratory symptoms that result in additional therapy.[11] Detailed medical history along with smoking history, comorbidities and medication history noted, and general and respiratory examination was to be done for every patient at the time of admission. SpO2 under room air, O2 requirement, Arterial blood gas (ABG) values, chest X-ray (CXR), hemogram values, creatinine levels, electrocardiography (ECG) findings, and ECHO findings at the time of admission were to be noted.

Blood sample was taken to analyses serum cTnI levels along with routine investigations with informed consent from each patient at initial point of care.

cTnI was estimated by immunochromatographic qualitative assay, DIAQUICK Troponin I cassette.

The DIAQUICK Troponin I Cassette is an immunochromatographic assay. It utilizes a combination of particle-conjugated anti-cTnl antibodies and a capture reagent to selectively detect cTnl in the whole blood, serum, or plasma. The minimum detection level is 1.0 ng/mL.

When the sample is added to the sample pad, it moves through the conjugate pad, where it mobilizes gold anti-cTnI conjugate, which is coated on the conjugate pad. Then, the mixture moves along the membrane by capillary action and reacts with anti-cTnI antibodies, which are coated on the test region. If cTnI is present in the sample at levels of 1.0 ng/mL or higher, a colored line appears in the test region. If cTnI is present at lower levels or is not present in the sample at all, the test region will remain colorless. The sample continues to move to the control region and forms a colored line, indicating that the test is working, and its result is valid. The minimum detection level is 1.0 ng/ml with sensitivity 95%, specificity 97%, and accuracy 90%.

Whether the patient was admitted in the ward or ICU, whether the patient required any ventilatory support (NIV or invasive ventilation), and duration of the stay in the hospital was all followed up. The end point of the follow-up is discharge or death.

Statistical methods

  • All continuous variables were represented as mean ± standard deviation if they were normally distributed. Otherwise, represented by median (interquartile range)
  • Categorical variables were represented by percentage
  • Comparison of normally distributed continuous variables between the two categories was done by independent sample t-test. Nonnormally distributed continuous variables were compared by Mann–Whitney U-test
  • Comparison of categorical variables was done by either Chi-square test/Fisher's exact test
  • Data entry was done in MS Excel Spreadsheet
  • Data analysis and validation of data were done by SPSS version 25.0 (IBM, Chicago, USA)
  • All P < 0.05 was considered statistically significant



  Observation and Results Top


During the study period, a total of 62 were included in the study, out of which 44 were male, and 18 were female [Table 1] and [Graph 1].[96]
Table 1: Classification of airflow limitation severity in chronic obstructive pulmonary disease (based on postbronchodilator forced expiratory volume in 1 s)


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[Table 2]
Table 2: ABCD assessment tool for chronic obstructive pulmonary disease


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[Table 3]
Table 3: Gender distribution


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Total age distribution

Out of the 62 patients, the age ranges from 42 to 88 years with mean of 63.5.

The BMI of the patients ranged from 14 to 27 with a mean of 21.9.

All the patients had spirometry-proven COPD according to the GOLD guidelines.

The duration of COPD ranges from 1 to 35 years with mean of 15.23.

Out of the 62 patients in the study, 46 patients were smokers and 16 were nonsmokers.

Out of the 46 smokers, smoking index ranged from 90 to 450 with a mean of 218.5.

Out of the 62 patients, 11 patients had significant biomass fuel exposure.

Out of the 62 patients, 57 were on regular inhaler use and 5 patients were not using inhalers.

Out of the 62 patients, 8 patients had alcoholism.







[Table 4]
Table 4: Distribution of patients according to age


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[Table 5]
Table 5: Percentage of smokers


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Comorbidities

Out of the 62 patients, 37 patients had systemic hypertension, 15 had diabetes mellitus, and 8 had coronary artery disease among various others.

Presenting complaint

The predominant symptom at presentation was breathing difficulty followed by cough, wheeze, and drowsiness.

The total WBC count ranged from 2000 cells/mm3 to 20,000 cells/mm3 with a mean of 9.73 cells/mm3.

Radiology

Out of the 62 patients, 35 patients had hyperinflated lung fields and 27 had increased bronchovascular markings on CXR.







[Table 6]
Table 6: Percentage with significant biomass fuel exposure


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[Table 7]
Table 7: Percentage with regular inhaler use


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[Table 8]
Table 8: Percentage with alcoholism


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Electrocardiography

Out of the 62 patients, 21 had ST depression, 7 had P pulmonale, 53 had tachycardia, and 2 had atrial fibrillation in ECG.

Echocardiogram

Out of the 62 patients, 14 patients had pulmonary artery hypertension (PAH). Based on the calculated RV systolic pressure, 7 had mild PAH, 6 had moderate PAH, and 1 had severe PAH.

The LV ejection fraction of patients in ECHO ranged from 35% to 65%, with a mean of 57.85%.

Hypoxemia and hypercarbia during acute exacerbation of chronic obstructive pulmonary disease

The SpO2 in room air ranged from 52 to 98 with a mean of 84% and 38 patients had SpO2 of less than 90% on admission.

Troponin I positivity in acute exacerbation of chronic obstructive pulmonary disease

Out of the 62 patients, 7 (prevalence = 11.3%) patients were tested to be TnI positive during exacerbation.

Out of the 62 patients, 15 patients received ventilatory support (10 received NIV and 4 received invasive ventilation).

The duration of hospitalization ranged from 3 to 12 days with a mean of 5.5.







Characteristics of patients with troponin I positivity

In conclusion, compared with the patients admitted with TnI negative, TnI-positive patients were of more prolonged duration of COPD, presence of PAH, lower SpO2 at room air and higher PaCO2 at presentation, increased requirement of ventilatory support with ICU care, and more duration of hospitalization. All of these were statistically significant


  Discussion Top


Our study was carried out in a tertiary care hospital in Southern India. A total of 62 patients were included in the study period from January 2018 to November 2019.

Analysis of results showed that majority of patients included in the study were male. Out of 62 patients enrolled in the study, 44 (71%) patients were male and 18 (29%) patients were female. This is comparable with the study published by Landis et al.[97] Out of the 62 patients, age ranges from 42 to 88 years with a mean of 63.5 and this is in accordance with the study done by Menezes et al.[98]







In our study, BMI of the patients ranged from 14 to 27 with a mean of 21.9 as comparable with study by Guo et al.[99] All the patients had Pulmonary function test (PFT)-proven COPD according to the GOLD guidelines. The duration of COPD ranges from 1 to 35 years with mean of 15.23.

Out of the 62 patients including in the study, 46 (74.2%) patients were smokers and 16 (25.8%) were nonsmokers and this is also comparable with Wheaton et al.,[100] Rahersion et al.,[101] and Terzihan et al.[102]

Out of the 46 smokers, smoking index ranged from 90 to 450 with a mean of 218.5 which is much lesser than the values from Llorde's et al. (1040),[103] Barthwal et al. (452),[104] and Targowski et al. (820).[105]







[Table 9]
Table 9: Percentage with systemic hypertension


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[Table 10]
Table 10: Percentage with diabetes mellitus


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[Table 11]
Table 11: Percentage with coronary artery disease


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[Table 12]
Table 12: Percentage of predominant presenting complaint


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[Table 13]
Table 13: Percentage with P pulmonale


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[Table 14]
Table 14: Percentage with tachycardia


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[Table 15]
Table 15: Percentage with segment depression


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[Table 16]
Table 16: Percentage with atrial fibrillation


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[Table 17]
Table 17: Percentage with pulmonary artery hypertension


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Out of the 62 patients, 8 (12.9%) patients are having significant biomass fuel exposure and this is concordance with the study by Salvi et al.[106]

Out of the 62 patients in our study, 57 were on regular inhaler use and 5 patients were not using inhalers. This is contrary to the outcomes according to Melani et al.[107] and Yawn et al.[108] in which good adherence to inhaler treatment along with proper technique was associated with decreased incidence of exacerbations.

In our study of 62 patients, 37 (24.2%) patients had systemic hypertension as the most common comorbidity in concordance with Greulich et al.,[109] Sin et al.,[37] and Kunhisaki et al.,[110] 15 (24.2%) had diabetes mellitus which is slightly lesser than according to Cebron et al.[111] (30%) and 21 (33.9%) had coronary artery disease which is slightly more compared to the study by Soriano et al.[112] (22%).

In ECG, out of the 62 patients, 21 (33.9%) had ST depression, 7 patients (11.3%) had P pulmonale, 53 (85.5%) had tachycardia, and 2 (3%) patients had atrial fibrillation. This is in contrast to study by Noorain et al.[9] where 38 (76%) had ST depression, 20 (34%) had P pulmonale, and 1 (2%) had atrial fibrillation.

In our study, 14 patients (22.5%) had PAH in ECHO (PASP >30) among with only one patient had severe PAH (7.1%). This is in accordance with the findings of Chaouat et al.[113] and Jyothula et al.[114]

Furthermore, in our study, 19 patients (30.6%) had LV dysfunction in ECHO which is in agreement with study results of Render et al.[115] and Connors et al.[116]



[Table 18]
Table 18: Severity of patients with pulmonary artery hypertension


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[Table 19]
Table 19: Percentage of troponin I positivity


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[Table 20]
Table 20: Percentage of patients received ventilatory support


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[Table 21]
Table 21: Duration of chronic obstructive pulmonary disease in percentile between troponin-positive and -negative patients


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[Table 22]
Table 22: Smoking index in percentile between troponin-positive and -negative patients


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[Table 23]
Table 23: Oxygen saturation in percentile between troponin-positive and -negative patients


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[Table 24]
Table 24: Partial pressure of carbon dioxide in percentile between troponin-positive and -negative patients


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In our patients in the study, the mean SpO2 on room air at admission is 84% and this is much lesser than Noorain et al.[9] (78.5%).

Out of the 62 patients, 15 (17%) patients received ventilator support and this is also lesser than Noorain et al.[9] (56%) and Gupta et al.[7] (36%).

The duration of hospitalization ranged from 3 to 12 days with a mean of 5.5, and this is in agreement with Seemungal et al.[17]

Out of the 62 patients, 7 (11.3%) patients were tested to be TnI positive during exacerbation. This is lesser than the results of Brekke et al. (27%), Noorain et al.[9] (38%), Baillard et al.[87] (18%), Gupta et al.[7] (34%), and Harvey et al. (25%).[91] The possible reason for this would be:

  • The test used for cTnI measurement in our study is a rapid, one-step, immunochromatographic qualitative assay and its detection limit is 1 ng/ml as compared with Youssef et al. (99%) and Gupta et al. (7%) in which the detection limit was very low as 0.01 ng/ml
  • The methodology in our study uses point-of-care, single testing for cTnI and does not use serial measurement to detect
  • The methodology in our study uses point-of-care, single testing for cTnI. It does not use serial measurement to detect Subsequent positivity which was done in studies done by Noorain et al.[9] (0 and after 1 day) supported by Carlton et al.,[117] Roffi et al.[118] (0 and 1 h measurement), and Muller et al.,[119] Than et al.[120] (0 and 2 h measurement).
  • Change of value – Delta criteria as per universal definition of acute MI.[121]




[Table 25]
Table 25: Age in percentile between troponin positive and negative patients


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[Table 26]
Table 26: Days of hospitalization in percentile between troponin positive and negative patients


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[Table 27]
Table 27: Presence of pulmonary artery hypertension in percentage between troponin positive and negative


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[Table 28]
Table 28: Need for ventilatory support in percentage between troponin positive and negative


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[Table 29]
Table 29: Intensive care unit admission in percentage between troponin positive and negative


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[Table 30]
Table 30: Presence of coronary artery disease in percentage between troponin positive and negative


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The patient age between cTnI + and cTnI − was not statistically significant and this in accordance with Baillard et al. and on contrary to Harvey and Hancox.[91]

The duration of COPD in between cTnI + and cTnI − was significant and this is in concordance with Noorain et al.[9]

The smoking index between cTnI + and cTn − was not statistically significant and is agreement with Baillard et al.[9] and Deveci et al.[122]

The comorbidities between cTnI + and cTnI − were not statistically significant as well and is in concordance with Gupta et al. but contrary to Youssef et al.[93] and Noorain et al.[9]

In our study, cTnI was significantly correlated with SpO2 and this correlated with findings from Noorain et al.,[9] Baillard et al.,[87] and Youssef et al.[93]

Regarding the PaCO2, the values between cTnI + and cTn − was statistically significant in our study and this is in agreement with Gupta et al. and Youssef et al. but contrary to the findings of Noorain et al.[9]

The difference in days of hospitalization between cTnI positive and cTnI negative was significant in our study, and this is in agreement with King et al.[123] and Youssef et al.[93] but contrary to the findings of Noorain et al.[9]

In our study, difference of percentage of P pulmonale and PAH between cTnI + and cTnI − was statistically significant and this in contrary to the findings of Noorain et al.,[9] Youssef et al.[93] and Gupta et al.,[7] but the severity of PAH is not statistically significant.

In our study, the need for ICU admission and ventilatory support in percentage between Tn-positive and Tn-negative patients was statistically significant and this in accordance with Noorain et al.[9]



[Table 31]
Table 31: Presence of P pulmonale (electrocardiogram) in percentage between troponin positive and negative


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[Table 32]
Table 32: Severity of pulmonary artery hypertension in percentage between troponin positive and negative


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[Table 33]
Table 33: Comparison of independent variables with troponin I-positive and troponin I-negative patients


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[Table 34]
Table 34: Comparison of categorical variables between cardiac troponin I-positive and troponin I-negative patients


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Limitation

  • The test used for cTnI measurement in our study is a rapid, one-step, immunochromatographic qualitative assay and its detection limit is 1 ng/ml as compared with Youssef et al. (99%) and Gupta et al. (7%) in which the detection limit was very low as 0.01 ng/ml
  • The methodology in our study uses point-of-care, single testing for cTnI and does not use serial measurement to detect
  • Subsequent positivity which was done in study done by Noorain et al.[9] (0 and after 1 day) supported by Carlton et al.,[117] Roffi et al.,[118](0 and 1 h measurement) and Muller et al.,[119] Than et al.[120] (0 and 1 h measurement)
  • Change of value – Delta criteria as per universal definition of acute MI[121]



  Conclusion Top


cTnI is elevated in a significant proportion of patients admitted with acute exacerbation of COPD. These patients had longer duration of COPD, increased presence of pulmonary hypertension, lower SpO2 on room air and higher PaCO2 at presentation, increased requirement of ventilatory support with ICU care, and more duration of hospitalization. Thus, cTnI can be used a prognostic marker in patients admitted with AECOPD.

Recommendation

To validate our findings in the study, we require large-scale, multicenter long-term randomized control trials.

Acknowledgment

Thanks to the Department of Respiratory Medicine, Apollo Hospitals, Chennai.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16], [Table 17], [Table 18], [Table 19], [Table 20], [Table 21], [Table 22], [Table 23], [Table 24], [Table 25], [Table 26], [Table 27], [Table 28], [Table 29], [Table 30], [Table 31], [Table 32], [Table 33], [Table 34]



 

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Abstract
Introduction
Cardiac Troponins
Aim and Objectives
Materials and Me...
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