Evaluation of serum level of uric acid among patients with exacerbation of asthma and patients with controlled asthma

Azita Tangestaninezhad¹, Seyyed Ali AlaviFoumani¹, Masoud Ghasemi¹, Alireza Jafarinezhad^1*

¹Inflammatory Lung Diseases Research Center, Department of Internal Medicine, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

^*Corresponding Author: Alireza Jafarinezhad

* Email: alireza.jafarinezhad.md@gmail.com

Abstract

Introduction: Evidence of increased serum uric acid (UA) levels during asthma exacerbations is still unclear. High levels of UA may lead to increased inflammation; in this regard, we aimed to investigate the level of UA and associated factors in patients with exacerbation of asthma attacks and those with controlled asthma.

Materials and Methods: In this study, demographical and clinical data from 300 patients (150 outpatients and 150 hospitalized patients) with asthma who were referred to Razi Hospital, Rasht, Iran, from August 2018 to March 2019 were collected. Also, the UA and spirometry parameters (FEV1, FEV1/FVC) were assessed for patients. All data were analyzed using SPSS version 21 considering a significant level<0.05.

Results: Among 300 patients with asthma, 158 were male, and 142 were female. A significant association was reported between gender, body mass index (BMI), history of smoking, opium consumption, alcohol consumption, number of asthma attacks, family history of asthma, and history of atopy among hospitalized and outpatients (P<0.05). In addition, there was a significant difference between the level of UA in the two groups at the beginning of treatment (P<0.05). Also, a significant difference between the level of UA in hospitalized patients at the beginning and the end of treatment was observed (P<0.05). In addition, a significant difference between the oxygen saturation level among two groups of outpatients and hospitalized patients at the beginning of treatment was seen (P<0.001).

Conclusion: According to our results, the level of UA might be used as a relative predictive factor in the severity of asthma attacks.

Keywords: Asthma, Chronic obstructive pulmonary disease, Outpatients, Hospitalized patients, Uric acid

Introduction

Asthma is a chronic inflammatory disease of the airways characterized by increased responsiveness of the tracheobronchial passages to various stimuli. Asthma occurs due to temporary blockage of airflow due to chronic inflammation of the airways, identified by periodic and reversible attacks of wheezing, shallow breathing, shortness of breath, and cough. From the etiological point of view, asthma is a heterogeneous disease that genetics, environment, and allergens contribute to the onset and continuation of it (1,2). The prevalence of asthma is increasing in many parts of the world, and it is estimated that 4-5% of the population of the USA has asthma. Bronchial asthma occurs at any age, with the most frequent onset at the early years of life (3).

Asthma is diagnosed according to some symptoms, physical examination, chest X-ray, and lung function diagnostic tests measuring FEV1, PEF, and most importantly, FEV1/FVC through spirometry (3,4). A disproportionate response of T-helper cells usually causes airway restriction in asthma type 2 (Th2) to allergens. Cytokines produced by Th2 are mainly responsible for regulating many features of asthma and lead to airway inflammation, excessive mucus secretion, and structural changes in the airway path (5,6).

Uric acid (UA) is a product of the purine metabolism pathway first recognized as a danger signal released from dying cells (7). It was reported that the level of UA was increased in the airways of asthmatic patients exposed to allergens. The administration of UA crystals with protein antigen leads to increased Th2 immunogenicity and clinical features of asthma through dendritic cell activation, splenic tyrosine kinase, and inositol triphosphate (IP3) kinase signaling (8).

These studies indicate that UA is an essential initiator and enhancer of Th2 immunogenetic in asthma, reflecting airway inflammation. In addition, strategies that target the inhibition of UA synthesis with allopurinol or the suppression of the uricase enzyme lead to a reduction in the production of Th2 progenitor cytokines, pulmonary inflammation, repair, and fibrosis (9,10). Hypoxia can explain the possible potential mechanism of the impact of UA on asthma during the exacerbation of asthma, which is induced by UA, oxidative stress, and inflammation-inducing lung tissue damage that leads to increased levels of UA. Also, high levels of UA may lead to increased inflammation that ultimately impairs lung function (11,12).

Previous studies have indicated that serum levels of UA increased in hypoxic conditions such as chronic heart failure, primary pulmonary hypertension, and chronic obstructive pulmonary disease (COPD) compared to hyperoxia/normoxia conditions (13–15). Moreover, the exact mechanism also occurs during the exacerbation of asthma and bronchospasm caused by it. However, evidence of increased serum levels of UA during asthma exacerbations is unclear; only a few studies have been conducted on this issue. In this regard, we aimed to compare the serum level of UA among patients with controlled asthma and patients with exacerbation of asthma attacks at the beginning of hospitalization and at the time of discharge from the hospital in Rasht, Iran.

Materials and Methods

Study design

This study collected demographical data and clinical characteristics of 300 patients (150 outpatients and 150 hospitalized patients) with asthma who were referred to Razi hospital, Rasht, Iran, from August 2018 to March 2019. Patients with incomplete data and a history of malignancies were excluded from the study. All data were recorded from the patients' archives. Asthma exacerbation was diagnosed based on GINA guidelines, which include a set of specific clinical findings, including relevant medical history, progressive increase in shortness of breath, cough, wheezing, chest tightness, pulse rate, respiratory rate, oxygen saturation, and peak flow measurement (16). The patients with lung diseases, in addition to asthma, suspected or confirmed malignancy, multiple disorders or infection, acute gastrointestinal bleeding, cardiovascular diseases, kidney failure, and consumption of foods containing large amounts of purine, were excluded from the study. This study was approved by the ethical committee at the Guilan University of Medical Science [IR.GUMS.REC.1397.357].

Variables

Collected data included age, gender, body mass index (BMI) as low weight (BMI<18.5 kg/m²), average weight (BMI=18.5–24.99 kg/m²), overweight (BMI=25–29.9 kg/m²), and obese (BMI≥30 kg/m²), a family history of asthma, keeping pets, history of exposure to allergens, history of smoking, alcohol consumption, opium consumption, underlying diseases, asthma medication, obstructive symptoms, sinusitis, mental illness, history of reflux, atopy, level of serum UA, and spirometry indexes such as FEV1 and FEV/FVC. In addition, the level of UV was measured by kit (Bionik, Iran) with the BT3500 (Biotecnica Instruments. SpA -Italy) auto-analyzer.

Statistical analysis

All data were analyzed using SPSS software version 21. The quantitative data were reported as mean ± standard deviation (SD), and qualitative data were also described as numbers and percentages. The normality was measured using the Shapiro-Wilk and Kolmogorov-Smirnov tests. The comparison of serum levels of UA in patients with exacerbation of asthma attacks and those with controlled asthma was measured using the independent t-test (Mann-Whitney if were non-parametric). The correlation between the serum level of UA and variables was measured using Pearson's correlation test (Spearman's if were non-parametric). The comparison of the level of UA in patients with exacerbation of asthma attack at the beginning of hospitalization and at the time of discharge was performed using paired t-test (Wilcoxon's if were non-parametric). Logistic regression was used to investigate the relationship between the level of UA and asthma considering the effects of other intervening variables. The statistical significance level of the data was defined as P<0.05.

Results

Demographical data and clinical characteristics of patients were demonstrated in Table 1. Of the 300 studied patients, 158 were male, and 142 were female, with a mean age of 60.19±16.48 years. The mean age of hospitalized patients was lower than outpatients, 56.96±17.15 years (24-90) and 60.19±15.16 years (27-86), respectively, but no statistically significant difference was reported (P=0.610) between the mean age of two groups. The mean BMI in hospitalized and outpatient groups was 78.78±18.98 kg/m² and 73.96±19.22 kg/m², respectively, representing a significant difference between the two groups (P=0.010). The average time of asthma diagnosis in outpatients and hospitalized groups was 88.19±117.71 months and 106.71±101.7 months, respectively (P=0.140).

Evaluating the presence or absence of daily exposure to occupational allergens among patients revealed that most hospitalized patients were exposed to allergens compared to the outpatients (P=0.001). Also, keeping pets was more frequent among hospitalized patients than outpatients (P<0.05). Most hospitalized patients had a history of opium consumption, and the frequency of smoking was significantly higher in hospitalized patients than in outpatients (P<0.001). There was a significant difference between the two groups based on alcohol consumption and a history of mental illness (P<0.05).

The average times of asthma attacks in hospitalized and outpatients were 2.02±1.27 months (0-8), and the mean age of 66.68±21.73 years old (1-50) during their lifetime (P<0.001). However, the frequency of hospital administration due to asthma attacks was significantly higher in the hospitalized group compared to the outpatients (57.12±87.78 vs. 2.09± 1.21, P=0.010). In addition, the prevalence of a family history of asthma and consuming asthma medication was higher among hospitalized patients (P<0.05). Also, pulmonary construction symptoms were highly reported in both groups, while the prevalence of atopy was significantly higher among hospitalized patients (P<0.001).

The mean serum level of UA was 4.82±1.19% mg/dL in the outpatient group; and in the group of hospitalized patients, at the beginning of the treatment, the mean serum level of UA was 7.31±1.85 mg/dL and at the end of treatment was 5.69±1.11 mg/dL (P<0.001), Figure 1. There was a significant difference between the serum level of UA in the two groups (P<0.001). The mean oxygen saturation level in the outpatient group was 91.14±1.81%, and in hospitalized patients at the beginning and the end of treatment, were 78.13±2.95% and 90.65±1.91%, respectively (P<0.001).

Evaluation of the level of FEV1 illustrated that in the group of outpatients, it was 65.59 ± 3.3%. In the group of hospitalized patients, at the beginning of the treatment, the mean serum level of UA was 69.95±44.2 mg/dL, and at the end of treatment was 94.76±62.2 mg/dL (P<0.001). Also, the level of FVC in the group of outpatients was 65.05±2.99, and in hospitalized patients at the beginning and the end of treatment, were 44.2±13.9 and 57.2±46.5, respectively (P<0.001).

Discussion

The present study evaluated the serum level of UA among patients with exacerbation of asthma attacks and controlled asthma. Most of the patients in the current study were middle-aged males (52.6%). Due to our findings, the level of UA in hospitalized patients was significantly higher than in outpatients. Also, the level of UA at the beginning of hospitalization was significantly higher than at the time of discharge, similar to other studies (17–19). In addition, our results illustrated that the level of UA was significantly different in the two groups regarding age, gender, BMI, a history of smoking and opium, alcohol consumption, and asthma medication (P<0.05).

This increase may be related to the asthma attack due to the inflammatory state caused by cell necrosis and apoptosis, followed by an increase in purine metabolites, including DNA and RNA. This increase in metabolites elevated the function of the xanthine oxidase (XO) enzyme, which results in higher levels of UA (20). Another mechanism that has been described as the increased UA following an asthma attack is the increase in the degeneration of adenosine three phosphates (ATP) and the increase in the production of UA by the XO enzyme following hypoxia that plays a diverse role in both acute and chronic lung inflammation (21,22). In addition, several studies have mentioned the relationship between the higher level of UA and the increase in the level of inflammatory cytokines such as C reactive protein (CRP), tumor necrosing factor (TNF), and interleukin-1 (IL-1), which are higher in the acute phase compared to the chronic phase (11,18,23).

The current study found no significant association between hospitalization frequency and UA level in the two groups (P>0.05). This finding suggests that UA levels may not be a reliable marker for predicting the likelihood of hospitalization in patients with asthma exacerbation or controlled asthma. While previous studies have suggested a potential link between UA and the incidence of asthma (24), our results indicate that other factors might play a more dominant role in determining hospitalization rates. This negative correlation implies higher UA levels may indicate poorer respiratory function and lower oxygen saturation levels. Moreover, there was a negative association between the level of UA and FEV1 and FVC. These findings align with previous research suggesting that UA could contribute to airway inflammation and obstruction, impairing lung function. While their result of the association between hospitalization frequency and UA level did not consistent with our study (18). However, it is essential to note that our study only establishes an association and does not establish a causal relationship.

A study by Lin et al. found a significant relationship between levels of UA and functional lung disorders (17). Other studies reported that the level of UA has an inverse association with spirometry indicators, primarily due to tissue hypoxia during the exacerbation of asthma that causes UA production, and secondly, because the increase in UA levels causes lung tissue inflammation and decreases lung function (25,26).

Recent studies illustrated the impact of the antioxidants such as vitamins E and C in reducing the level of UA, which can indicate that the level of UA may be changed due to cardiovascular diseases, diet patterns, lifestyle, kidney function, and familial purine metabolism problems (27,28). Moreover, the age of the patients can affect the level of UA, which explains the variety of results in different studies (27). Also, some studies have pointed out that vitamin D, E, and C deficiency affects the exacerbation of asthma attacks (29,30).

Limitations

One limitation of this study is referring to the recall bias of the patients to report the duration time of asthma. Also, the impact of consuming supplements was not investigated in the current.

Conclusions

According to our results, the level of UA at the beginning of hospitalization was significantly higher than outpatients and at the time of discharge, which might be used as a predictive factor for asthma severity assessment.

Author contribution

AT, SAAF, and AJ conceptualization, the original draft writing, investigation, and formal analysis; AT and AJ conceptualization, supervision, and project administration; SAAF and AJ conceptualization, and project administration; AT, and MGH investigation; AJ and MGH writing including reviewing and editing and investigation.

Conflict of interest

The authors reported no potential conflict of interest.

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P-value	Test statistics	Standardized regression coefficient	Standard error	Regression coefficient	Variables
<0.001	13.45	0.61	0.18	2.44	Outpatients/Hospitalized patients
0.027	-2.23	-0.182	0.219	-0.491	Use of medication