|Year : 2018 | Volume
| Issue : 1 | Page : 1-6
Evaluation of fractioned nitric oxide in chronic cough patients
Y Yildiz, M Igde
Department of Pediatric Allergy and Immunology, Samsun Training and Research Hospital, Samsun, Turkey
|Date of Acceptance||19-Dec-2016|
|Date of Web Publication||06-Feb-2018|
Dr. Y Yildiz
Department of Pediatrics, Samsun Training and Research Hospital, Samsun
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Cough exceeding 3-8 weeks was defined as chronic cough in various guides. Asthma is the most common cause of chronic-specific cough. Causes other than asthma include prolonged bacterial bronchitis and upper airway cough syndrome (UACS). Nitric oxide (NO) causes vascular smooth muscle relaxation, bronchodilation, and oxidant effects via its metabolite, peroxynitrite. An increase in NO results in inflammation, vasodilatation, and bronchial edema. Materials and Methods: The study group included 90 patients aged 6-17 years selected from individuals presenting to the Pediatric Immunology and Allergic Diseases Clinic with cough persisting for 4 weeks and 30 other patients representing to the control group. Patients with a history of premature birth and long-term ventilatory support, neuromotor retardation, or chronic lung and heart disease received systemic corticosteroid therapy in the previous 4 weeks, a chest deformity, with any chronic disease or received immunotherapy were excluded from the study. Results: The most common diagnosis among the 90 patients in this study was asthma, observed in 27 (30%). Fractional exhaled NO values were highest in the asthma group at 39.5 ± 26.6 parts per billion (ppb) and lowest in the UACS group at 11.6 ± 4.0 ppb. Values in the control group were 17.8 ± 11.1 ppb. The differences between the groups were statistically significant (P < 0.001). Conclusion: Fractional exhaled NO measurement can be used as a quick and reliable diagnostic method in patients presenting with chronic cough due to its high positive predictive value, its practical nature, the fact that it is a noninvasive method and that it does not require the use of medication.
Keywords: Asthma, chronic cough, fractional exhaled nitric oxide
|How to cite this article:|
Yildiz Y, Igde M. Evaluation of fractioned nitric oxide in chronic cough patients. Niger J Clin Pract 2018;21:1-6
| Introduction|| |
Cough “is not a disease, but a vital reflex” and is the most important of the natural defense mechanisms that eliminate particles and secretions from the airways and protect the lower air passages. It is also an important symptom of respiratory tract conditions and one of the most common causes of hospital admissions among children.,
Coughs lasting less than 3 weeks are defined as acute, while those persisting for 3-8 weeks are described as chronic.,, The majority of patients in studies on the prevalence of chronic cough is younger children
(mean age 2-3 years), and the proportion is higher among preschool children. Recurrent cough is also more common in males than in females. A total of 80% of the patients have been reported to make more than five and 53% to make 10 or more presentations to physicians before presenting to a chest diseases specialist and increasingly more consultations are required for children with chronic cough., Varying results have been obtained in studies investigating the etiology of chronic cough in children. When the underlying conditions are divided into specific and nonspecific causes, the most common conditions seen in the general population are nonspecific causes and particularly prolonged bacterial bronchitis (PBB), upper airway cough syndrome, and natural healing. Asthma is the most common cause of chronic specific cough. Specific causes other than asthma include gastroesophageal reflux, infections such as tuberculosis and pertussis, primary ciliary dyskinesia, tracheobronchomalacia, and tracheoesophageal fistula.
Tests such as posteroanterior lung radiography, the respiratory function test (RFT), the skin prick test, immunoglobulin E (IgE) level measurement, reflux scintigraphy, and 24-h pH monitoring, and so on. are used for the diagnosis of diseases underlying chronic cough. The fractional exhaled nitric oxide (FeNO) is another test increasingly used in recent times for the diagnosis of asthma, among the most common causes of specific chronic cough.
Nitric oxide (NO) is synthesized as a result of the oxidation of the amino acid L-arginine with the enzyme nitric oxide synthase in smooth muscle, endothelial cells, and many other mammalian cells. NO performs numerous functions, including blood pressure regulation and reduction of platelet adhesion and aggregation, as well as exhibiting proinflammatory and anti-inflammatory effects.,
Studies demonstrate that NO plays critical roles in such phenomena as antigen presentation and supply, differentiation of T cell functions in the acquired immune system known as the adaptive immune system and the development of the cell-mediated immune system.,,
The product of the reaction of NO with superoxide, peroxynitrite provides bactericidal and cytotoxic effects against tumor cells. It also increases bronchial blood flow through vasodilation, thereby causing airway edema.
FeNO refers to NO in exhaled air in parts per billion (ppb), corresponding to nanoliters per liter. FeNO can be influenced by many factors. FeNO levels in children have been reported to increase with age., Similarly, FeNO levels are higher in men compared with women.
FeNO levels have been reported to decrease in reverse proportion to height. Greater body mass index (BMI) is associated with higher FeNO levels. It has also been reported that FeNO levels decrease following exercise, that smoking reduces FeNO levels by 30%-60%, and that viral infections of the upper and lower respiratory system increase FeNO levels by 50%-150%. FeNO levels decline with the use of inhaled and/or oral steroids (fluticasone, methylprednisolone).
| Aim|| |
A total of 44% of patients presenting with chronic cough also exhibit wheezing/hissing in addition to cough, 60% of whom are diagnosed with asthma. Many international guidelines recommend that FeNO can be used in the diagnosis of asthma.,,, We, therefore, think that FeNO measurement can represent a useful diagnostic technique at time of diagnosis in 30%-50% of patients with chronic cough. Although numerous studies involving children have investigated the etiology of chronic cough and NO in asthmatic patients, none have investigated FeNO in children with chronic cough. The aim of this study was to investigate FeNO measurement as a practical, fast, and noninvasive technique that can assist the clinician with diagnosis in patients presenting with chronic cough and that can predict the success of treatment.
| Materials and Methods|| |
Patients aged 6-17 years presenting with cough persisting for more than 4 weeks to the pediatric immunology and allergic diseases polyclinic between November 2013 and October 2014 and 30 other patients representing control subjects were included in the study. Patients who were born prematurely, received long-term ventilation, with neuromotor growth retardation, received systemic corticosteroid therapy within the previous 4 weeks, with chest deformity or any chronic condition (such as asthma, cystic fibrosis, hypertension, autoimmunity, and malignancy), or receiving immunotherapy were excluded.
Diagnosis and treatment
FeNO was measured in all patients and those diagnostic tests (the respiratory function test, the skin prick test, and IgE level measurement etc.) that were indicated were performed. Eosinophil numbers exceeding 4% of the total white cell count was regarded as positive eosinophilia, total IgE > 150 IU/mL as elevated IgE, changes of 12% or more in peak expiratory flow (PEF) measurement following administration of 0.15 mg/kg salbutamol by nebulizer as RFT/reversibility positivity, and erythema in the skin positive control edema (histamine hydrochloride 1 mg/mL) formed by the half urticarial papules or creating larger diameter papules was regarded as positive skin prick test. The tuberculin skin test, mycobacterial culture and acid-resistant bacilli in fasting gastric fluid were performed on patients suspected of tuberculosis.
In line with the modified asthma predictive index, in the presence of one major risk factor (asthma and/or atopic dermatitis in a parent, atopic dermatitis in the patient or sensitivity to aerosols in the patient) or two minor risk factors (food sensitivity, wheezing in the absence of the common cold, or eosinophil count ≥ 4%) in children with recurring wheezing, the presence of more than two wheezing and/or dyspnea attacks responding to bronchodilator therapy and/or improvement greater than 12% in forced expiratory volume in the first second (FEV1) with spirometry were regarded as asthma. Clinical findings (history of contact, prolonged fever recalcitrant to nonspecific therapy, and loss of appetite or weight), radiological findings, and tuberculin skin test positivity greater than 15 mm were evaluated as tuberculosis. Retrosternal burning discomfort, normal posteroanterior lung radiography, absence of daily PEF variation, cough failing to respond to treatment, and response to domperidone and ranitidine therapy within 2 weeks were regarded as gastroesophageal reflux disease. Upper respiratory tract cough syndrome was diagnosed in the presence of hyperemia in the pharyngeal or nasal mucosa, findings such as postnasal discharge and response to nasal saline solution and oral or nasal decongestant therapy. PBB was diagnosed in children with isolated cough if this resolved in 2-4 weeks with appropriate antibiotics and in the absence of alternative causes of specific cough. Resolution of cough without treatment while under observation was defined as natural healing. Presence of coarse, wheezing daytime cough in which organic causes were excluded, cough ceasing with activity or night-time sleep, and the absence of any underlying diseases in the tests performed were defined as psychogenic cough.
| FeNO Measurement|| |
For evaluation of FeNO level, American Thoracic Society's the ''Interpretation of exhaled nitric oxide levels (FeNO) for clinical applications'' is sampled guide.
Factors affecting FeNO levels, such as age, sex, BMI, and exposure to cigarettes were recorded. A NIOX-MINO ® device produced by Aerocrine AB (Sweden) was used for online FeNO measurement (FeNO were measured directly exhaled breath).
| Study Protocol|| |
The American College of Chest Physicians 2006 guideline ''Introduction to the Diagnosis and Management of Cough'' was adopted for chronic cough. Patients were reassessed at weeks 2 and 4 of treatment. Ethical committee approval from the Educational Planning Commission of the Samsun Training and Research Hospital, Turkey was received on 11/07/2013 (No. 2013/13).
Data were analyzed on IBM SPSS 21.0 software. Significance levels were set at P < 0.05.
| Results|| |
Females constituted 48.3% (n = 58) of the subjects in the study and males 51.7% (n = 62). No significant differences were observed between the groups, including the control group (P = 0.46). Mean age was 10.8 ± 3.6 (6-17) years, with no significant difference between the control and patient groups (P = 0.53). Mean age at onset of cough was 10.5 ± 3.67 (4-17) years, and mean duration of cough was 12.7 ± 30.6 (4-240) weeks. Etiology and epidemiological characteristics of the patients in the study are shown by groups in [Table 1]. The most frequent cause of chronic cough in the patients in this study was asthma.
Examination of the positivity rates of the diagnostic tests administered to the patients presenting to our clinic with chronic cough revealed significant differences in skin tests and IgE elevations [Table 2].
Girls in the control group had a mean FeNO of 20.6 ± 13.9 (10-50) ppb compared with 15.4 ± 7.6 (9-41) ppb in boys, and no significant difference was observed between the genders (P = 0.13). Similarly, no correlation was observed between FeNO and age or BMI in the patients in the control group (P values 0.16 and 0.26, respectively).
Mean FeNO was 21.5 ± 19.3 (5-104) ppb in the total patient group, 21.8 ± 18.5 (6-103) ppb in girls and 21.3 ± 20.3 (5-104) ppb in boys, with no significant differences observed (P = 0.51). Similarly, no relationship was observed between FeNO and age or BMI in the patient group (P values 0.24 and 0.9, respectively). The mean FeNO value in the control group was 17.03 ± 11.02 (9-50) ppb compared with 21.52 ± 19.33 (5-104) ppb in the total patient group. The difference was not statistically significant (P = 0.97).
Intragroup analysis revealed the highest FeNO value, 39.5 ± 26.6 ppb (6-104), in the asthma group and a statistically significant difference was observed among all the groups (P < 0.001). The groups were then compared pair wise, which demonstrated that only the asthma group differed from the other groups (P value 0.007 after correction).
Positivity rates of the diagnostic tests administered in all the diagnosis groups were investigated, and intergroup differences were observed in RFT/reversibility positivity and mean FeNO values [Table 3]. Consistent with the purpose of the study, the reliability of the diagnostic tests in terms of asthma, the most common cause of chronic cough, was evaluated using receiver operating characteristics analysis [Table 4].
|Table 4: Reliability values of diagnostic tests in the etiology of chronic cough|
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| Discussion|| |
Most of the conditions that lead to chronic cough are treatable. Diagnosis of the underlying condition is therefore of critical importance to treatment. Asthma has been identified as the most common underlying condition in most studies investigating diseases involved in the etiology of chronic cough (3.7%-64.1%).,,, Current guidelines published by the European and American Thoracic Societies emphasize that asthma should be considered the primary cause in differential diagnosis of recurring/chronic cough., In our study, asthma was the most significant cause in 30% of cases.
The depth of laboratory analyses in cases of children with chronic cough depends on findings and suspected etiology. Tests including serum total IgE, peripheral blood eosinophil count, and skin tests can be used to evaluate atopy accompanying chronic cough and in patients in whom atopic asthma is suspected.,, One of the most important of these tests is RFT/reversibility. RFT and reversibility tests were performed in all cases and as needed, respectively, for patients who presented with chronic cough in our study.
When used in the diagnosis of patients presenting with chronic cough, the tests listed above are time-consuming (RFT/reversibility), invasive (skin test and blood tests), require bronchoscopy (broncheoalveolar lavage) and involve high costs. In contrast, measurement of FeNO, a marker of inflammation in airways, is simple, convenient, and noninvasive. We observed a difference between FeNO levels in the control and patient groups, although this was not statistically significant [Table 3]. When the patient groups were studied individually, mean FeNO values were highest in the asthma group, the difference being statistically significant.
In the diagnosis of asthma, RFT reveals variability as a marker of bronchial narrowing, airway hypersensitivity, and reversibility. It confirms and facilitates the diagnosis of asthma. Numerous international societies and guidelines also report that FeNO measurement can be used in diagnosing asthma.,, Previous studies have determined a correlation between RFT/reversibility and FeNO or the process of diagnosing asthma and FeNO. One study of asthma patients during acute asthma attack with no clinical signs enrolled as a control group reported FeNO levels of 8.2 ± 0.5 ppb in the control group, 8.8 ± 1.5 ppb in stable asthma patients, and 15.0 ± 1.0 ppb in acute asthma patients, and proposed FeNO as a promising clinical tool in evaluating acute asthma attacks.
RFT and FeNO measurements have been shown to be successful in demonstrating inflammation in the airways. These two parameters have also been shown to be correlated, and asthmatic children can be distinguished from nonasthmatic children using FeNO., Another study investigating the relationship between FeNO levels and bronchial hyperreactivity and pulmonary functions observed a significant negative correlation between FeNO and % FEVı.
The statistical significance and power of FeNO measurement in diagnosing asthma as the most common factor in the etiology of chronic cough has also been studied previously. Research has demonstrated that asthmatic cases can be distinguished from nonasthmatic patients using FeNO measurement with 85% sensitivity and 90% specificity. Another study reported 72.2% sensitivity, 75% specificity, 96.2% positive predictive value (PPV), and 23% negative predictive value (NPV) in determining asthma when a threshold of 25 ppb was adopted for FeNO. In our study, FeNO measurement exhibited 78% sensitivity, 92% specificity, 82% PPV, and 91% NPV in the diagnosis of asthma. RFT/reversibility tests exhibited 81% sensitivity, 89% specificity, 76% PPV, and 92% NPV. NO measurement in exhaled air and RFT/reversibility tests, regarded as the gold standard, yielded almost identical results in the diagnosis of asthma in patients presenting with chronic cough.
| Conclusion|| |
A number of different conditions are involved in the etiology of chronic cough. In asthma, the most common of these clinical conditions, FeNO levels increase in contrast to other diseases. FeNO measurement can represent a useful diagnostic tool at time of first presentation in 30%-50% of patients with chronic cough. FeNO measurement can be used as a fast and safe diagnostic method in patients presenting with chronic cough since it is noninvasive, does not require drug administration, and has a high positive predictive power. However, its use in routine practice should also be investigated in terms of cost-effectiveness.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Massie J. Cough in children: When does it matter? Paediatr Respir Rev 2006;7:9-14.
Chang AB, Landau LI, Van Asperen PP, Glasgow NJ, Robertson CF, Marchant JM. Cough in children: Definitions and clinical evaluation. Med J Aust 2006;184:398-403.
Chang AB. Chronic non-specific cough in children. Pediatrics and child health 2008;18:333-9.
Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al.
An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011;184:602-15.
Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest 2006;129:260-83.
Leconte S, Paulus D, Degryse J. Prolonged cough in children: A summary of the Belgian primary care clinical guideline. Prim Care Respir J 2008;17:206-11.
Chang AB. Pediatric cough: Children are not miniature adults. Lung 2010;188:33-40.
Alving K, Janson C, Nordvall L. Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children. Respir Res 2006;20:67-74.
Irwin RS. Introduction to the diagnosis and management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006;129:25-7.
de Jongste JC, Shields MD. Cough. 2: Chronic cough in children, Thorax. 2003;58:998-1003.
Chow PY, Ng DK. Chronic cough in children. Singapore Med J 2004;45:462-8.
Acembekaroǧlu S. Seasonal change in exhaled nitric oxide level in patient with allergic asthma susceptible to inhalant allergens. 2012. Available from: https://tez.yok.gov.tr
Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat Immunol 2013;14:52-60.
Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H. Signaling and transcription in T helper development. Annu Rev Immunol 2000;18:451-94.
Pore D, Mahata N, Chakrabarti MK. Outer membrane protein a (Ompa) of Shigella flexneri 2a links innate and adaptive immunity in atlr2-dependent manner and involvement of Il-12 and nitric oxide. J Biol Chem 2012;287:12589-601.
Documents ATS. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J Respir Crit Care Med 2005;171:912-30.
Avital A, Uwyyed K, Berkman N, Bar-Yishay E, Godfrey S, Springer C. Exhaled nitric oxide is age-dependent in asthma. Pediatr Pulmonol 2003;36:433-8.
Kharitonov SA, Yates D, Barnes PJ. Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections. Eur Respir J 1995;8:295-7.
Wong GW, Liu EK, Leung TF, Yung E, Ko FW, Hui DS. High levels and gender difference of exhaled nitric oxide in Chinese schoolchildren. Clin Exp Allergy 2005;35:889-93.
De Winter-de Groot KM, Van der Ent CK, Prins I, Tersmette JM. Exhaled nitric oxide: The missing link between asthma and obesity. J Allergy Clin Immunol 2005;115:419-20.
Cho YJ, Lim HJ, Park JS, Lee JH, Lee CT, Yoon HI. Measurement of fractional exhaled nitric oxide in stable bronchiectasis. Tuberc Respir Dis 2013;74:7-14.
Palazzo RM, Haddad GG. Diagnostic approach to respiratory disease. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson Textbook of Pediatrics. 15th ed. Philadelphia: W.B. Saunders; 2004;1243-64.
Fitch PS, Brown V, Schock BC, Taylor R, Ennis M, Shields MD. Chronic cough in children: Bronchoalveolar lavage findings. Eur Respir J 2000;16:1109-14.
Goldsobel AB, Chipps BE. Cough in the pediatric population. J Pediatr 2010;156:352-8.
Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al.
An official ATS clinical practice guideline: Interpretation of exhaled nitric oxide levels (FeNO) for clinical applications. Am J Respir Crit Care Med 2011;184:602-15.
Chang AB, Robertson CF, van Asperen PP, Glasgow NJ, Masters IB, Teoh L, et al.
A cough algorithm for chronic cough in children: A multicenter, randomized controlled study. Pediatrics 2013;131:1576-83.
Marchant JM, Chang AB. Re: Evaluation and outcome of young children with chronic cough. Chest 2006;130:1279-80.
Massie J. Cough in children: When does it matter. Paediatr Respir Rev 2006;7:9-14.
Keskin O. The importance of exhaled nitric oxide in asthma and its correlation with host and environmental factors. 2010; Available from: https://tez.yok.gov.tr
Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: A randomized controlled trial. Am J Respir Crit Care Med 2005;172:831-6.
Crater SE, Peters EJ, Martin ML, Murphy AW, Mills TA. Expired nitric oxide and airway obstruction in asthma patients with an acute exacerbation. Am J Respir Crit Care Med 1999;159:806-11.
Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide 'for the diagnosis of asthma. Chest 2003;123:751-6.
Silvestri M, Sabatini F, Sale R, Defilippi AC, Fregonese L, Battistini, et al
. Correlations between exhaled nitric oxide levels, blood eosinophilia, and airway obstruction reversibility in childhood asthma are detectable only in atopic individuals. Pediatr. Pulmonol 2003;35:358-63.
[Table 1], [Table 2], [Table 3], [Table 4]