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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 67  |  Issue : 1  |  Page : 46-49

Plasma asymmetric dimethylarginine in childhood asthma exacerbation


1 Department of Chest, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission10-Jul-2017
Date of Acceptance26-Sep-2017
Date of Web Publication21-Mar-2018

Correspondence Address:
Adel S Bediwy
Department of Chest Diseases, Tanta University Hospital, Tanta, 33633
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejcdt.ejcdt_30_17

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  Abstract 

Background Asymmetric dimethylarginine (ADMA) is a new marker of inflammation in different inflammatory disorders. Bronchial asthma as a chronic disease of inflammatory nature is related to an expanded levels of numerous markers of inflammation which are used to assess the degree of severity of childhood asthma and might be the object of new therapeutic alternatives aiming at enhancing the management of such diseases.
Aim The aim of this study was to evaluate the plasma levels of ADMA in asthmatic children during asthma exacerbation and to assess the relationship between these levels and the degree of asthma control during the past 6 months.
Patients and methods A total of 250 asthmatic children, aged 6–12 years, with acute exacerbation were evaluated during their visit to emergency room unit for serum ADMA (measured by high-performance liquid chromatography) and peak expiratory flow rate before receiving any treatment. They were 125 males and 125 females. Moreover, 100 participants were taken as controls.
Results Plasma ADMA was significantly higher in asthmatic children compared with the control group. It was higher in asthmatic children who had poorer response to initial therapy at emergency room. Plasma ADMA showed significant negative correlation with peak expiratory flow rate and significant positive correlation with a number of asthma exacerbations during the past 6 months
Conclusion Plasma ADMA is elevated during exacerbation of childhood asthma. High levels above 2.83 μmol/l can predict poor response to initial therapy at emergency room and the need for hospitalization with sensitivity and specificity of 91.5 and 84.25%, respectively.

Keywords: asthma, asthma exacerbation, asymmetric dimethylarginine


How to cite this article:
Bediwy AS, Hassan SM, Ganna SA, El-Najjar MR. Plasma asymmetric dimethylarginine in childhood asthma exacerbation. Egypt J Chest Dis Tuberc 2018;67:46-9

How to cite this URL:
Bediwy AS, Hassan SM, Ganna SA, El-Najjar MR. Plasma asymmetric dimethylarginine in childhood asthma exacerbation. Egypt J Chest Dis Tuberc [serial online] 2018 [cited 2018 Nov 12];67:46-9. Available from: http://www.ejcdt.eg.net/text.asp?2018/67/1/46/228134


  Introduction Top


Bronchial asthma is the most common chronic disease of childhood, with significant morbidity and negative effect on lifestyle, including school-days lost, emergency department [emergency room (ER)] visits, and hospitalization, beside the long-term adverse effects of different medications [1].

Asthma exacerbation is a leading cause that can increase the risk of asthma mortality [2]. Despite the great advances in understanding asthma pathophysiology and development of new therapeutic agents, the prevalence of asthma is increasing worldwide, necessitating more researches for detection of new inflammatory mediators and therapeutic options [3].

Although the exact pathophysiological factors of asthma are still unclear, airway inflammation and oxidative stress are the major mechanisms involved in pathogenesis of asthma, so monitoring of inflammatory biomarkers may improve the control of asthma [1].

l-Arginine metabolism recently emerged as a major pathway in the maintenance of airways tone and functions, mainly through nitric oxide (NO) production via nitric oxide synthase (NOS) [3].

Asymmetric dimethylarginine (ADMA) is a metabolite derived from proteolysis of methylated tissue proteins and has been implicated in the pathogenesis of asthma [4].

It is an l-arginine analog that competitively inhibits NOS, leading to decreased NO synthesis. Higher levels of ADMA can also uncouple NOS activity promoting superoxide (O) formation. Both mechanisms have negative effects on asthmatic patients, promoting airway narrowing.

Most studies evaluating the role of ADMA in adults have reported conflicting results.

Up to our best knowledge, this is the first paper evaluating the level of ADMA in childhood asthma exacerbation and its link to asthma control.

The aim of this work was to evaluate the plasma level of ADMA in asthmatic children during exacerbation compared with control participants and to find a relationship between these levels and degree of asthma control during the past 6 months.


  Patients and methods Top


This prospective controlled study was carried out in Pediatrics and Chest Diseases Departments, Tanta University Hospital, Egypt, between June 2014 and June 2016.

We examined 250 children diagnosed as having mild–moderate persistent degree of asthma (group II) attending the ER with asthma exacerbations, and they were recruited successfully for our study. Diagnosis of asthma depended on Global Initiative for Asthma guidelines and National Asthma Education and Prevention Programme, 2007.

Moreover, 100 healthy participants (group I) of matched age and sex were included in the study as a control group.

The local ethics committee of our center has approved the research protocol, and written informed consents were obtained from parents of all children.

Inclusion criteria

  1. Age range was 6–12 years.
  2. All cases diagnosed previously as having mild–moderate persistent asthma at least for 1 year before inclusion in the study.
  3. Patients who came to ER for asthma exacerbations.


Exclusion criteria

  1. Patients with other pulmonary diseases – for example, cystic fibrosis and bronchiectasis.
  2. Patients with chronic medical disorders – for example, heart, renal and endocrinal diseases.
  3. Usage of systemic steroids for 2 months before the study.


Children of control group had no chest troubles and negative history of steroid use in the past 6 months. All of them had negative personal and family history of wheezy chest, asthma, or nebulizer use before.

All included patients had detailed history taking and thorough clinical examination. Peak expiratory flow rate (PEFR) was measured in all of them.

Blood samples were taken from all patients in ER during acute asthma exacerbation before any rescue medication was given to them.

Patients were given standard treatment of asthma exacerbation and then reassessed after 1 h to evaluate response to initial therapy. Children with good response did not need admission, with no return to ER for 1 week.

Determination of plasma asymmetric dimethylarginine level

Under complete aseptic conditions, venous samples were collected into prechilled EDTA-containing tubes, which were placed immediately on ice and centrifuged within 20 min at 4°C. Coded plasma samples were stored at −80°C for ADMA analysis at the end of the study. ADMA was assayed by high-performance liquid chromatography with a lower limit of detection of 0.1 μmol/l and an assayed range of 0.1–8.0 μmol/l [5]. The intra-assay and interassay coefficients of variation were ∼1.2 and ∼2.0, respectively.

Statistical analysis

All quantitative data were expressed as mean±SD. Data were tested for normal distribution, and Kruskal–Wallis test and Mann–Whitney test were used to evaluate significance of difference among groups. All the analyses were conducted using SPSS 20.0 (SPSS Inc., Chicago, Illinois, USA). Statistical significance level was set at P value less than or equal to 0.05.


  Results Top


A total of 250 children with mild–moderate persistent asthma (group II) with acute exacerbation and 100 control children (group I) were included in our study.

Demographic data and PEFR of both patients and control groups are demonstrated in [Table 1].
Table 1 Demographic data and peak expiratory flow rate of the studied patients

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There was a nonsignificant difference between patients and control group regarding age, male/female ratio, and BMI; however, asthmatic patients showed significant higher blood eosinophil ratio (7.2±2.3 vs. 2±0.6) and significant lower PEFR (49.5±7.1 vs. 94.0±7.9) compared with the control group.

Plasma level of ADMA was significantly higher (2.7±0.9 μmol/l) in asthmatic children during exacerbation than ADMA level in control group (0.55±0.2 μmol/l) (P=0.001), as shown in [Table 2].
Table 2 Comparison between asthmatic patient during exacerbation and control group according to their plasma asymmetric dimethylarginine level (μmol/l)

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Plasma ADMA levels showed significant negative correlation with PEFR and significant positive correlation with numbers of asthma exacerbations during the past 6 months before recruitment in the study ([Table 3]).
Table 3 Correlation between plasma asymmetric dimethylarginine and both peak expiratory flow rate and numbers of asthma exacerbations during past 6 months

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After initial therapy in ER, 63% of asthmatic children showed good response and 37% showed poor response. On reviewing plasma levels of ADMA of both of them, it was noticed that it was significantly higher in asthmatic children with poor response than those with good response (3.1±0.5 vs. 2.3±0.6 μmol/l, respectively, with t=6.5 and P=0.006).

Receiver operating characteristic curve analysis showed that plasma ADMA level had a sensitivity of 91.5% (95% confidence interval: 70.21–98.73%) and a specificity of 84.25% (95% confidence interval: 62.7–95.1) for differentiating between good and poor response to initial therapy at ER at an optimal cutoff value of 2.83 μmol/l. The likelihood ratio positive (LR+) was 5.421, and the likelihood ratio negative (LR−) was 0.113. The area under the receiver operating characteristic curve was 0.9444 ([Figure 1]).
Figure 1 ROC curve showing plasma ADMA for differentiation between good and poor responder to initial therapy at ER with a sensitivity of 91.5% and a specificity of 84.25% at an optimal cutoff value of 2.83 μmol/l.

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  Discussion Top


ADMA has long been found to be associated with renal failure [6],[7] and cardiovascular diseases [8],[9]; however, we recently reported increased levels of ADMA in asthma and cystic fibrosis airways, which likely contributes to NO imbalance and respiratory dysfunction. Most of these studies were done in adults, with presentation of conflicting results [10],[11],[12].

We limited our study to asthmatic children aged 6–14 years to avoid viral-induced bronchospasm, which is common among children younger than 6 years, and also we can measure PEFR easily.

In our study, plasma level of ADMA during exacerbation and before receiving any rescue treatment was significantly higher compared with control participants. So, progressive increasing of plasma ADMA may be a contributing factor for asthma exacerbation. Although the exact mechanism is still unknown, dysregulation of l-arginine metabolism may be the cause. l-Arginine metabolism, including the NO synthase and arginase pathways, is important in the maintenance of airway function, and accumulation of ADMA results in a functionally relevant shift of l-arginine breakdown by NO synthases toward the arginase pathway, which contributes to airway obstruction in asthmatic patients.

A couple of studies on ADMA measurement in plasma are present, although with contrasting results. Riccioni et al. [13] found that low plasma concentrations of ADMA are associated with asthma, whereas Holguin et al. [14] reported high plasma levels of ADMA in asthmatic patients.

Carraro et al. [15] demonstrated that ADMA can be measured in exhaled breath condensate in asthmatic children as a reliable marker of asthma; however, the included patients were quite heterogenous, including patients with different severity and treatment. As we try to make our patient sample more homogenous, we exclude asthmatic children with mild intermittent and severe persistent asthma, and we choose the more common population − that is, asthmatic children with mild and moderate persistent asthma.

Moreover, we found that plasma ADMA was even higher in children who showed poor response to initial therapy at the ER, reflecting its importance in evaluating drug response in asthmatic children. Plasma ADMA was able to differentiate between good and poor response to initial ER therapy with sensitivity of 91.5% and specificity of 84.25% at an optimal cutoff value of 2.83 μmol/l.

Moreover, plasma ADMA showed a significant negative correlation with PEFR and significant positive correlation with the number of asthma exacerbations during the past 6 months.

More multicenter studies are needed on a larger number of asthmatic children for more clarification of the role of ADMA in pediatric asthma and the effects of different asthma medications on plasma ADMA level.


  Conclusion Top


Plasma ADMA is elevated during acute childhood asthma exacerbation in comparison with control participants. High levels above 2.83 μmol/l can expect poor response to initial therapy at ER and need for hospitalization, with sensitivity of 91.5% and specificity of 84.25%.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004; 59:469–478.  Back to cited text no. 1
    
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North ML, Scott JA. l-Arginine metabolism in the lung: reciprocal regulation of the NOS and arginase pathways. Open Nitric Oxide J 2011; 3(Suppl 1):48–54.  Back to cited text no. 3
    
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Schwedhelm E, Boger RH. The role of asymmetric and symmetric dimethylarginines in renal disease. Nat Rev Nephrol 2011; 7:275–285.  Back to cited text no. 7
    
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Kurz K, Teerlink T, Sarcletti M, Weiss G, Zangerle R, Fuchs D. Plasma concentrations of the cardiovascular risk factor asymmetric dimethylarginine (ADMA) are increased in patients with HIV-1 infection and correlate with immune activation markers. Pharmacol Res 2009; 60:508–514.  Back to cited text no. 8
    
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Boger RH, Maas R, Schulze F, Schwedhelm E. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality − an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 2009; 60:481–487.  Back to cited text no. 9
    
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Grasemann H, Al-Saleh S, Scott JA, Shehnaz D, Mehl A, Amin R et al. Asymmetric dimethylarginine contributes to airway nitric oxide deficiency in patients with cystic fibrosis. Am J Respir Crit Care Med 2011; 183:1363–1368.  Back to cited text no. 10
    
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Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P et al. Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med 2011; 184:779–785.  Back to cited text no. 11
    
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Scott JA, Grasemann H. Asymmetric dimethylarginine: a disease marker for asthma? Chest 2013; 144:367–368.  Back to cited text no. 12
    
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Riccioni G, Bucciarelli V, Verini M, Consilvio NP. ADMA, SDMA, l-arginine and nitric oxide in allergic pediatric bronchila asthma. J Biol Regul Homeost Agents 2012; 26:561–566.  Back to cited text no. 13
    
14.
Holguin F, Comhair SA, Hazen SL, Khatri SS. An association between l-arginine/asymmetric dimethyl arginine balance, obesity and the age of asthma onset phenotype. Am J Respir Crit Care Med 2013; 187:153–159.  Back to cited text no. 14
    
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Carraro S, Giordano G, Piacentini G. Asymetric dimethyl arginine in exhaled breath condensate and serum of children with asthma. Chest 2013; 144: 405–410.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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