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ORIGINAL ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 6  |  Page : 658-664  

Serum uric acid and clinical outcome of patients with acute exacerbation of chronic obstructive pulmonary disease


1 Department of Tuberculosis and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Diseases, New Delhi; Department of Pulmonary Medicine, AIIMS, Raipur, Chhattisgarh, India
2 Department of Tuberculosis and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
3 Department of Biochemistry, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India

Date of Submission21-Sep-2019
Date of Decision29-Oct-2019
Date of Acceptance03-Mar-2020
Date of Web Publication6-Nov-2020

Correspondence Address:
Amartya Chakraborti
Room Number 6, Doctors Hostel, Department of Tuberculosis and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Diseases, Sri Aurobindo Marg, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_261_19

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  Abstract 


Introduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and India contributes a significant and growing percentage of COPD mortality. Chronic hypoxia is a known condition causing tissue inflammation which may lead to an increased uric acid synthesis due to an increased RNA-DNA breakdown. Studies have shown the relationship between uric acid and adverse clinical outcomes in COPD. Data are lacking regarding this from the Indian subcontinent for which this study was undertaken. Materials and Methods: A prospective observational study was carried out at a tertiary respiratory care hospital for approximately 1 year to enroll patients admitted with acute exacerbation of COPD. Patients were divided into two groups with high and normal serum uric acid and were followed up for 30 days from admission. Following clinical outcomes were looked at duration of hospital stay, intensive care unit (ICU) admission, need for noninvasive ventilation (NIV)/invasive mechanical ventilation (IMV), mortality. Results: A total of 135 patients were enrolled (88 with normal and 47 with high serum uric acid levels). Patients with high serum uric acid had longer hospital stay (17.65 ± 4.41 vs. 11.65 ± 4.9 days), higher rates of ICU admission (60% vs. 21%), use of NIV/IMV (95% vs. 57%) and mortality (17% vs. 9%). Negative correlation was seen between serum uric acid and FEV1% predicted values in patients (r = −0.4, P = 0.017). Multiple logistic regression showed that high serum uric acid level was an independent risk factor for worse outcomes in all clinical parameters mentioned above. Conclusion: Serum uric acid is a widely available test which is economical can be used in stratifying the COPD patients who are more prone to adverse outcomes and may need intensive management. This will lead to proper resource utilization and patient management in a developing country like India.

Keywords: Acute exacerbation chronic obstructive pulmonary disease, mortality, noninvasive ventilation, serum uric acid


How to cite this article:
Patanwar S, Chakraborti A, Kumar L, Vohra V, Tayal D. Serum uric acid and clinical outcome of patients with acute exacerbation of chronic obstructive pulmonary disease. Med J DY Patil Vidyapeeth 2020;13:658-64

How to cite this URL:
Patanwar S, Chakraborti A, Kumar L, Vohra V, Tayal D. Serum uric acid and clinical outcome of patients with acute exacerbation of chronic obstructive pulmonary disease. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Dec 2];13:658-64. Available from: https://www.mjdrdypv.org/text.asp?2020/13/6/658/300138




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing.[1] India contributes a significant and growing percentage of COPD mortality, which is estimated to be the highest among the world.[2] More than 3 million people died of COPD in 2005, corresponding to 5% of all deaths globally, and it is estimated to be the third-leading cause of death by 2030.[3] Most of the information available on COPD prevalence, morbidity, and mortality come from high-income countries. Even in those countries, accurate epidemiologic data on COPD are difficult and expensive to collect. However, it is known that low- and middle-income countries already shoulder much of the burden of COPD with almost 90% of COPD deaths taking place in these countries.[4],[5] Hypoxia is a condition known to lead to ischemia, which may lead to an increased uric acid synthesis due to an increased RNA-DNA breakdown, resulting in an increased purine concentration.[6] As reported by Braghiroli et al., hyperuricemia due to hypoxia-induced ATP degradation is seen in patients with COPD.[7] Sato et al. studied the patients of COPD who were on home oxygen therapy and found that there was a significant increase in the mortality of patients who had increased serum uric acid levels.[8] Garcia-Pachon et al. in their study found a significant association of serum uric acid to creatinine ratio with spirometry values in stable COPD.[9] Patients with the serum uric acid to creatinine ratio above the median value had lower FVC and a higher level of dyspnea. Recent studies done by Fukuhara et al. proved that there is a significant relationship between serum uric acid and airflow limitation in COPD patients.[10] Embarak et al. and Bartziokas et al. studied the association of serum uric acid and outcome in AECOPD patients and concluded that there is the possible role of serum uric acid as a biomarker for predicting outcome in COPD patients.[11],[12]

In view of various studies, there is a relation of serum uric acid and the outcome of disease in the patients suffering from COPD; hence, this study was conducted. The results of this study have increased our understanding regarding the role of serum uric acid in COPD in the Indian population. As serum uric acid is a widely available test which is routinely done, easy to interpret and economical; hence, it can be used in identifying the COPD patients who are more prone to adverse outcomes and may need prompt and intensive management.

Objectives

To study the association of serum uric acid levels and outcome of patients hospitalized with AECOPD in terms of:

  1. Length of hospital stay
  2. Need for intensive care unit (ICU) admission within 30 days of initial admission for treatment
  3. Need for noninvasive ventilation (NIV)/invasive ventilation within 30 days of admission
  4. Mortality in patients within 30 days of admission.



  Materials and Methods Top


  • Study design: Prospective observational study
  • Study period: Approximately 1 year
  • Setting: National Institute of Tuberculosis and Respiratory Diseases, New Delhi.


Study sample

Criteria for inclusion

Subjects between 40 and 65 years of age with the diagnosis of acute exacerbation of COPD (newly diagnosed/follow-up) admitted through emergency or outpatient department (OPD).

Exclusion criteria

  • Refusal to participate in the study
  • History of active respiratory disorders other than COPD
  • Patient on uricosuric drugs
  • Patients with a history of: congestive cardiac failure, hypertension, chronic renal failure, alcoholic liver diseases, malignancies, gout.


Methods

All the patients admitted to the National Institute of Tuberculosis and Respiratory Diseases (NITRD) under Unit III in casualty and wards with AECOPD who gave informed consent were included in the study. Patients were subjected to the following:

  1. A thorough assessment of medical history. History of the number of exacerbations over the last 1 year was asked from subjects and mean of the number of exacerbations were calculated separately for high and normal serum uric acid subjects
  2. Full clinical examination
  3. Plain chest radiography
  4. Electrocardiograph
  5. ABG (arterial blood gas)
  6. Blood samples were collected from each patient at the time of admission and sent for routine blood investigations including complete blood count, kidney function tests, liver function tests, and serum electrolytes along with serum uric acid
  7. Patients were managed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines[1]
  8. Length of hospital stay of subjects was recorded in days and the mean duration of admission in days was calculated for high serum uric acid and normal serum uric acid subjects
  9. The clinical outcome was assessed at the end of 30 days, either by direct observation if the patient was admitted or else telephonicall.


Length of hospital stay

Need for NIV/invasive mechanical ventilation (IMV).

ICU admission for AECOPD within 30 days.

Mortality in patients within 30 days of admission. After discharge from the hospital, the patient was followed up in OPD or telephonically for 30 days of admission to determine rates of mortality.

Protocol for collection of sample

Samples for serum uric acid from the patients selected for the study were collected at the time of admission before any intervention taken for the patient. A volume of 2 ml of blood were collected in red top plain vacutainer. After clot formation sample was centrifuged at 2000 rpm for 15 min. Serum was separated and collected in the secondary tube for uric acid estimation on an autoanalyzer. Serum uric acid was estimated on autoanalyzer HITACHI–H-902 and using standard kits, used for quantitative determination in human serum.

Protocol for pulmonary function test

The diagnosis and classification of airflow limitation were based on postbronchodilator spirometry in a stable condition, that is, in the past 6 months and at least 4 weeks before admission from the patients' records or 4–8 weeks after discharge.

Pulmonary function tests

Spirometry

It was done by a dry rolling seal electronic spirometer (Morgan Transfer Test Model C or Medisoft, Spiro Air model. They were reported in absolute volumes as well as percent predicted based on regression equations used in our laboratory. Patients were first familiarized with the equipment and personnel of the laboratory. Spirometry measurements included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, maximum mid-expiratory flow rate (FEF25-75), peak expiratory flow rate, maximum voluntary ventilation.

Sample size

This was a time-bound observational study. The minimum patients to be enrolled were calculated form the admission data over the past 3 years. Care was taken to look into the admission records and rule outpatients with the added diagnosis of congestive heart failure, hypertension, ischemic heart disease, renal, and hepatic impairment along with COPD. According to the past 3 years of data, the number of patients admitted for acute exacerbation of COPD in the National Institute of Tuberculosis and Respiratory c- (2011–2012)- 525, (2012–2013)- 515, (2013–2014)- 520 patients. Hence, total patients in this 3 years were 525 + 515 + 520 = 1560. The average number of patients in a year.

1560/3 ≈ 520

The average number of patients admitting in Unit III – 520/4 ≈ 130 (as there are four units in our hospital managing admissions).

We enrolled 135 total patients in our study over an approximate time of 1 year.

Statistical analysis

The present study was a prospective observational study. The data were represented using frequency distribution with the diagrammatic presentation. Statistical analysis was performed using Statistical Package for the Social Studies (SPSS) for Windows, version 20, IBM Corporation, USA.

Ethical approval

Ethical clearance was taken from the ethical committee of NITRD, New Delhi.


  Results Top


A total of 135 patients were enrolled in the study, and demographics were studied after dividing them into groups of patients having high serum uric acid levels (47/135) and normal uric acid levels (88/135). There were no statistically significant differences among these two groups based on mean age, sex ratios, current smoking status, and BMI. The difference was seen in the higher average number of hospital admissions in the past year for exacerbations and average fev1 in patients with high serum uric acid levels [Table 1]. Pearson correlation revealed a negative relationship between FEV1% percentage predicted values and serum uric acid levels (r = −0.404, P = 0.017).
Table 1: Difference between clinical parameters between patients having high and low serum uric acid levels

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High serum uric acid levels were associated with worse clinical outcomes: longer hospital stay, higher rates of ICU admission, and the use of NIV/IMV. Higher rates of mortality at 30 days were also seen in patients with high serum uric acid levels [Table 2]. Although the hospital stay duration was greater in patients with high serum uric acid levels, time to death among them who expired was significantly lower (5.55 ± 4.03) than that in expired patients of normal serum uric acid group (12.33 ± 8.50), P value being 0.015. This difference is shown in the Kaplan–Maier survival curve in [Figure 1]. A multiple regression analysis was performed to look into the various risk factors responsible for worse clinical outcomes in our patients, serum uric acid is one of them [Table 3]. The other factors included age, smoking status, number of admissions in the past year, TLC, FEV1(% predicted), GOLD stage, hypercapnia or hypoxemia on ABG, and pulse oximetry at the time of admission. Serum uric acid emerged as an independent risk factor for poor prognosis in all of the clinical outcome parameters [Table 3].
Table 2: Difference in clinical outcome parameters between the study groups

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Figure 1: Kaplan–Meier survival curve in which Group A are the patients with high serum uric acid levels while Group B are patients with normal serum uric acid levels. Time is given in days. The survival curves of Group A and Group B diverge quickly and the gap maximises by the day 20 implying that majority of the expiry in the high serum uric acid group occured earlier than day 20 postadmission

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Table 3: Multivariate analysis showing association with various risk factors and adverse clinical outcome parameters

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  Discussion Top


This study was done to look into the association of raised serum uric acid with various clinical outcomes of acute exacerbations of COPD. In human beings, due to absence if the rasburicase enzyme, uric acid is not degraded and is present in high amounts in blood, measuring up to 50 times than that of the normal blood levels in nonprimate animals. This is usually beneficial to humans because uric acid is one of the most powerful antioxidants in the body. It neutralizes reactive oxygen species generated during normal metabolism and in cases of inflammation and prevents lipid peroxidation.[13],[14] Furthermore, uric acid can play a particularly important role in COPD because α1-antitrypsin is protected from nitration by uric acid in vitro.[15] Consequently, high uric acid levels are expected in cases of COPD with frequent severe exacerbations due to repeated events of hypoxia and inflammation. Severe exacerbations were defined as those requiring hospital admission. In our study, the frequency of hospital admissions in the past year was significantly higher in patients with high serum uric acid than with patients with normal serum uric acid levels (P < 0.05). Similar results were seen in a study done by Embarak et al. which showed patients with high serum uric acid levels had more hospital admissions for exacerbations than patients with normal serum uric acid in a year (P < 0.05).[11] In the study by Nicks et al., however low serum uric acid levels were associated with more severe COPD and hence exacerbations.[16] This finding can be reconciled by the fact that all the patients enrolled in the study were smokers (at least 10 pack-years smoking history) and this may be acted as a confounding factor. Smoking is known to decrease levels of antioxidants in the body including serum uric acid, maybe leading to the low serum uric acid levels in patients in the above-mentioned study.[17],[18] Bhatia et al. found a positive correlation between the number of exacerbations and serum uric acid levels.[19] Durmus Kocak et al. stated in their study that the patients who had frequent exacerbations had higher mean serum uric acid levels.[20] It has also been found that there are increased levels of endothelin-1found in patients with hyperuricemia which can lead to exacerbations.[21] Furthermore, pro-inflammatory effects of uric acid in terms of TNF-alpha activation have also been described.[22] In the study by Bartziokias et al., it was seen in the Cox regression analysis that serum uric acid levels was an independent risk factor for future hospital admissions in COPD patients.[12] This finding is further corroborated in the study by Kahnert et al. in which it was found that a 2 mg/dl increase in uric acid levels lead to a 5% higher chance that a patient will land up in the frequent exacerbator group.[23] In this study, we also see that the increase in serum uric acid level is associated with increased disease severity (in the form of the GOLD stage) and airflow limitation (in the form of a negative correlation with FEV1). This in part can explain the severity of exacerbations and the increase in the frequency of hospitalization in these patients. In the Takahata study done in 2011, spirometric values like FVC% predicted and FEV1% predicted were found to be inversely associated with high serum uric acid values.[24] We believe that the severity of airflow limitation is the chief factor for the high rates of ICU admission in this subgroup of patients in our study (60%). Airflow limitation in the face of acute exacerbation lands the patient in type 1 or type 2 respiratory failure requiring NIV/IMV in our ICU. Consequently, we find that 70% of admitted patients with high serum uric acid levels received NIV/IMV support their stay in hospital. This proportion is higher than the rate of ICU admission because as per our hospital policy for clinically stable patients not requiring intensive management, there is provision for NIV support in wards. In the study done by Embark et al., number of patients with high serum uric acid levels requiring ICU admission was (24%) higher than those with normal serum uric acid 3 (4.6%).[11] In the study of Bartziokas et al., 24 (16.2%) of patients with high serum uric acid required ICU admission which was higher than of patients with normal serum uric acid 4 (2.4%).[12] We are a tertiary respiratory care hospital in the national capital and a referral center for pulmonary disorders. As a result, we receive a high percentage of clinically unstable referral cases who consequently require ICU admission. We believe that this has led to a higher percentage (60%) of patients in our study group being admitted to the ICU. Studies done by Embarak et al. and Bartziokas et al. also demonstrate a higher proportion of patients with high serum uric acid levels requiring the use of NIV within 30 days of hospital stay (44% and 31.8%, respectively).[11],[12] The study included both patients requiring noninvasive and invasive ventilation, which is probably the reason for the higher percentage of patients requiring interventions. The negative association with uric acid and spirometric values can be explained by the fact that in patients with low spirometric values, impaired lung function leads to a state of recurrent hypoxia. This leads to a cascade of events leading to both systemic and local inflammation leading to rise in the serum uric acid levels.[25],[26] Furthermore, persistently, low lung function may lead to the development of secondary pulmonary hypertension and right ventricular dysfunction, both of which are known to be associated with high serum uric acid levels.[27],[28] Serum uric acid is a known prognostic marker for patients with pulmonary hypertension. In our study, the average duration of hospital stay in patients with high serum uric levels was found to be significantly higher (17.68 + 4.4) than patients with normal serum uric acid levels (11.65 + 4.65). Severe airflow limitation requiring a longer duration of medication and complications and higher ICU admission rates in this subgroup of patients may have led to the increased average hospital stay. Increased duration of hospital stay, ICU admission and use of IMV carries with it the risk of development of hospital-acquired pneumonia and ventilator-associated pneumonia and sepsis and various other complications. Consequently, this leads to an increased risk of mortality in patients with high serum uric acid. In this study, the mortality among high serum uric acid subjects (9 [19%]) was observed to be higher than normal serum uric acid patients (6 [7%]) with statistically significant P = 0.013. Serum uric acid values were independently associated with mortality in the multiple logistic regression analysis. A study done by Embaraket al also reported similar results with mortality of 9 (18%) in patients of high serum uric acid.[11] Bartziokas et al. stated that in patients with higher serum uric acid has increased mortality risk at 30 days compared to those with low serum uric acid levels (P < 0.001).[12] Galamay et al. also found that serum uric acid levels at admission are an independent risk factor for 30-day mortality in patients with acute exacerbation of COPD.[29] In Kaplan–Meier analysis we see that in patients with higher serum uric acid levels, mortality occurs earlier (P < 0.05) in the 30-day study period. This leads to the realization that uric acid is a risk factor for early mortality and patients with increased levels coming to our care have grave prognosis and require urgent intensive care. However, we must add that although at the time of admission, these patients did not have any major extrapulmonary organ derangement, during the hospital stay patients developed acute kidney injury (AKI), hepatic failure which may have added to the risk of mortality. This was compounded by the risk posed by sepsis which led to MODS (multiorgan disorder syndrome). There is no strong evidence to point that high uric acid level at the time of admission is a predictor of mortality in patients suffering from sepsis.[30] However, studies show that increased serum uric acid with sepsis at the time of admission is associated with worse prognosis with increased risk of AKI and acute respiratory distress syndrome.[31] It is evident that uric acid is part of a complex interplay of factors such as sepsis, AKI, metabolic stress, hypoxia, inflammation which ultimately lead to the grim prognosis of the patient. Further large scale studies with appropriately chosen control groups are required to further delineate its role and importance as a veritable prognostic marker.

Serum uric acid is an easily available biochemical test, which is also cheap. In a developing country like in India, its regular use in stratifying patients at the time of admission can immensely help in managing high-risk exacerbators with prompt intensive care. This can lead to decrease in mortality and ICU admissions and proper resource utilization. These patients should also be more carefully and frequently followed up in OPD to ensure proper compliance. In the study by Kahnert et al., COPD patients with high serum uric acid on hypouricemic medications had higher 6MWD and higher FVC% (although statistically nonsignificant, P = 0.06) values.[24] This lights the way for future research into the foray of using hypouricemia drugs in the management of COPD.

Limitations

First, the follow-up period in our study is 30 days and is not adequate to fully look into the outcomes of patients with high uric acid levels. Furthermore, the method of follow-up in some cases was the telephonic conversation which may have led to under-reporting of exacerbations. Another limitation was that females were underrepresented in our study who usually have lower uric acid levels. We did not divide the patient groups into having sepsis or not having sepsis during the follow-up. This would have helped us to define the importance of high uric acid levels in predicting prognosis in patients who developed organ dysfunction following florid sepsis with respect to those who did not have sepsis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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