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Doppler echocardiographic evaluation of pulmonary arterial pressure in children with allergic rhinitis
International Journal of Pediatric Otorhinolaryngology 60 (2001) 21 – 27 www.elsevier.com/locate/ijporl
Doppler echocardiographic evaluation of pulmonary arterial pressure in children with allergic rhinitis Hasan Yu¨ksel *, S¸enol Cos¸kun, Ali Onag˘ Department of Pediatrics, Medical Faculty, Celal Bayar U8 ni6ersity, Manisa, Turkey Received 30 January 2001; received in revised form 23 April 2001; accepted 24 April 2001
Abstract In children, persistent upper airway obstruction may lead to increased pulmonary arterial pressure (PAP). Allergic rhinitis (AR) is one of the frequent cause of persisting upper airway obstruction by nasal blockage in childhood. Regular use of nasal topical corticosteroids are effective in reducing nasal blockage and obstruction. However, whether symptomatic children with AR have increased PAP and curative effect of topical steroids are not known. The aims of this study were to clarify whether children having active symptoms of AR have increased PAP and to investigate the curative effect of reducing nasal obstruction by topical corticosteroids. Twenty-three children, aged between 5 and 16, diagnosed as AR, consisted of 17 seasonal AR (SAR) and seven perennial AR (PAR), were included in the study. Nineteen age and sex matched healthy children were received as controls. PAP was measured by using Doppler echocardiography in all subjects and symptom scores of AR were recorded in rhinitis group. After first evaluation, nasal steroid, budesonid, was given to rhinitis group for three months. Mean systolic PAP was 33.4 93.1 for children with AR mmHg and 23.6 94.3 mmHg for the control group. The difference was statistically significant (PB 0.05). Mean systolic PAP of children with PAR was significantly higher than children with SAR (PB 0.05). In rhinitis group, mean PAP decreased significantly after relief of upper airway obstruction by nasal corticosteroid therapy to normal level of 24.9 93.6 mmHg (P B 0.05). Our results showed that children with AR may have significantly higher PAP than healthy subjects and decreased to normal levels after relieving nasal blockage by nasal corticosteroids. Nevertheless, Doppler echocardiography is a safe, non-invasive and practical tool for cardiac investigation of children with AR. Therefore, in symptomatic period, evaluation of PAP of children with AR by using Doppler echocardiography may be useful in the planning and following of their therapy. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Allergic-rhinitis; Children; Pulmonary-arterial-pressure
1. Introduction * Corresponding author. Present address: 244 Sokak No: 10/2 D: 14, 35040 Bornova-I: zmir, Turkey. Tel.: + 90-2323436968; fax: + 90-236-2370213. E-mail address: [email protected] (H. Yu¨ksel).
Persistent or chronic upper airway obstruction may lead to cardiovascular deterioration by increasing pulmonary arterial pressure (PAP) in childhood [1]. Adenotonsillar hypertrophy charac-
0165-5876/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 5 8 7 6 ( 0 1 ) 0 0 5 0 0 - 6
22
H. Yu¨ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
terized by nasal blockage, upper airway obstruction, mandatory mouth breathing and recurrent upper respiratory infection is known as the most common cause of increased PAP due to chronic upper airway obstruction in childhood [2]. It was demonstrated earlier that increased PAP and cor pulmonale in children with adenotonsillar hypertrophy could successfully be reversed after relief of upper airway obstruction by adenoidectomy [3,4]. Adenotonsillar hypertrophy results in nasopharyngeal obstruction and upper airway resistance syndrome [5]. Then compensation of insufficient nasal ventilation causes mandatory mouth breathing [4,6]. However, since mouth breathing does not provide sufficient air supply during night-time, insufficient inflation results in alveolar hypoventilation, hypoxemia and hypercarbia [6,7]. Therefore, upper airway obstruction may lead to hypoxic pulmonary vasoconstriction. Pulmonary arterial hypertension occurs as a result of vasopressor mediator release from pulmonary vascular bed and increased endothelial sensitivity to vasoconstrictor mediators owing to sustained upper airway obstruction [8– 10]. Nocturnal hypoxemia and hypercarbia may cause obstructive sleep apnea syndrome (OSA), snoring, hyponasal speech, nocturnal enuresis, obesity and growth retardation [6,11,12]. Allergic rhinitis (AR) is the most common allergic disease of upper respiratory tract and is characterized by IgE mediated allergic response to environmental allergens and immunocellular infiltration in nasal mucosa. Prevalence of AR among children is approximately 6– 15% and increasing gradually [13,14]. The most characteristic symptoms are nasal blockage related to nasal mucosal inflammation, sneezing, nasal itching and watery rhinorrhoea [15– 17]. According to the time of exposure, AR can be subdivided into seasonal (SAR), related to pollens, and perennial (PAR), related to house dust allergens and animal dander [16]. In children with AR, mandatory mouth breathing, snoring, hyponasal speech and occasionally OSA may develop due to nasal blockage and upper airway obstruction as occur in subjects with adenotonsillar hypertrophy [14,18]. However, possible upper airway resistance syndrome and increased PAP due to AR has not
been studied earlier. The main cause of upper airway resistance syndrome and nasal blockage in AR is eosinophilic inflammation of nasal mucosa and edema due to IgE mediated persistent allergic reaction [19]. Thus, rational therapy of nasal obstruction in this disorder is topical anti-inflammatory therapy [20]. The most potent nasal topical anti-inflammatory agents are topical corticosteroids such as budesonide [21]. Also, whether there is any change in PAP after reducing nasal obstruction by using nasal corticosteroids has not been studied earlier. In this study, the children who were affected by upper respiratory obstruction due to AR and the effects of nasal corticosteroids on those were evaluated by clinical and laboratory investigations. The aims were to clarify whether children with active symptoms of AR have increased PAP and to demonstrate whether there is any beneficial effect of nasal topical corticosteroids on this possible complication. 2. Materials and methods
2.1. Study group Twenty-four children diagnosed as AR and followed-up in our Paediatric Allergy outpatientclinic were enrolled into the study. They were composed of 17 subjects with SAR and seven subjects with PAR according to their history, clinical and laboratory criteria. The definition of AR was made by using International Consensus Statement on the management of AR [22]. Therefore, subjects with AR were diagnosed as those individuals with a characteristic history of perennial or seasonal symptoms of AR (rhinorrhoea, sneezing, nasal obstruction and pruritis) and who also had skin sensitization to perennial or seasonal allergens. All our subjects had seasonal or perennial symptom history of AR for at least 2 years. Also, they had positive family history of atopy, high serum IgE levels (Diagnostic Automation Inc., CA, USA), positive skin-prick tests responses (] 3 mm wheal diameter) to pollen extracts of grass mix, as seasonal allergens, or Dermatophagoides Pteronyssinus and Farinea, as perennial allergens (Allergopharma JGK, Rein-
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
bek, Germany). Exclusion criteria included presence of other causes of nasal obstruction such as nasal polyps and rhinosinusitis. We also excluded children, who were using nasal topical or systemic corticosteroids, antihistamines or other anti-allergic drugs within earlier 2 months. To compare PAP values, 19 non-atopic, healthy, sex and age matched children were included as a control group. Table 1 shows demographic and clinical characteristics of study and control groups.
3. Study design After the inclusion and exclusion criteria were examined, baseline symptom score was noted and PAP was measured by using Doppler echocardiography. On this visit, families and children were instructed to administer twice a day nasal corticosteroid, budesonide (Rhinocort Aqua Nasal Spray, AstraZeneca Co., USA), by using a dose of 200 mg per day (one puff in each nostril), in the morning and evening for 8 weeks. At the end of the study, their symptoms scores and PAP values were evaluated and noted. All subjects were warned to admit to the clinic, when there was any exacerbation in their symptoms.
3.1. Symptom scoring To score nasal obstruction symptoms of children with AR, parents and subjects were asked by
23
using standard criteria which are presented in Table 2. The criteria included upper airway obstruction symptoms such as nasal blockage, snoring, mouth-breathing during sleep and daytime, hyponasal voice. Scores of symptoms were between ‘0’ and ‘5’ points.
3.2. Doppler echocardiography After routine cardiovascular examination, they were also examined by using Doppler echocardiography to obtain PAP values. Doppler echocardiography was performed using 2-D Colored-Doppler Echocardiography (Image Point, Hewlett-Packard Co, California, USA) applied with 2.5 MHz transducer. Systolic PAP was obtained from maximum pressure gradient between right ventricle and right atrium. It was determined with the Bernoulli equation by using the peak velocity of the tricuspid regurgitant jet. Peak velocity of tricuspid regurgitant jet was recorded by continuous wave Doppler echocardiography. Four-chamber view of heart was used for this echocardiographic examination. Color Doppler imaging was used for determination of the correct angle of regurgitant jet. To determine right atrium pressure, inspiratory collapse of inferior vena cava was used. When the diameter of inferior vena cava decreased more than 50% during inspiration, right atrium pressure was accepted as 10 mmHg. However, if this decreasing was less than 50%, right atrium pressure was
Table 1 Demographic and clinical characteristics of subjects Characteristics
Allergic rhinitis (n = 24)
Controls (n = 19)
P
Sex (F/M) SAR (n =17)a PAR (n = 7)b 5/2 Age (year) Symptom duration (year) Positive family history of atopy (%) High serum IgE Positive SPTc
9/5 10/9 5–16 (10.393.5) 2–6 (2.99 1.7) 22 (92) All All
\0.05 6–14 (9.8 92.7) – – –
\0.05 – – – –
a
Seasonal AR. Perennial AR. c Skin prick test. b
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
24
Table 2 Scoring nasal obstruction symptoms of children with allergic rhinitis Symptom ¡ score
0
1
2
3
4
5
Nasal blockage Mouth breathing Hyponasal voice Snoring Restless sleeping
No No No No No
Rarely Rarely Rarely Almost never Rarely
Mild Mild intermittent Occasionally Rarely Occasionally
Moderate Moderate intermittent Intermittent Intermittent Rather frequently
Severe Frequently Frequently Frequently Frequently
Very serious Always Always Every day Every day
accepted as increased. PAP was calculated by using pressure gradient as mentioned above and right atrium pressure as described earlier [23].
3.3. Statistics PAP values of study and control groups were analyzed by using unequal variance t-test. Preand post treatment symptom scores and PAP values of study group were compared by using equal variance t-test. P-value was accepted as significant less than 0.05.
4. Results
children with PAR had higher mean systolic PAP than children with SAR. Values were 35.29 3.9 and 31.59 2.7 mmHg, respectively, (P B0.05). Mean systolic PAP of study group significantly decreased to the level of 24.99 3.6 mmHg at the end of study (PB 0.05). Also, both PAP values of children with PAR and SAR were significantly decreased by nasal topical therapy. Post treatment PAP levels of both patients were 26.69 3.7 and 24.39 2.9 mmHg, respectively. Fig. 1 shows mean levels of systolic PAP of groups. No significantly correlation were obtained between systolic PAP levels and symptom scores (rB 0.25). All subjects had no other additional echocardiographic pathology.
4.1. Demographic and clinic characteristics 5. Discussion The mean age of the study group was 10.39 3.5 years. There were no significant differences between the age and sex characteristics of the study and control groups (Table 1). Mean duration of symptoms was more than 2 years in study group and a high percentage of these had positive family history of atopy (Table 1). Mean pre-treatment symptom score of these children was 3.69 1.4 per patient and significantly decreased to 1.19 0.5 per patient at the end of eight weeks of nasal topical corticosteroid therapy (P B0.05).
4.2. Pulmonary arterial pressure Mean pre-treatment systolic PAP of study group with 33.49 3.1 mmHg was significantly higher than in healthy control which was 23.69 4.3 mmHg (P B 0.05). When compared with mean systolic PAP of subjects with PAR and SAR, the
Persistent or chronic upper airway obstruction are believed to lead to increased PAP, pulmonary hypertension, cor pulmonale and moreover acute right heart failure [1,24]. Adenotonsillar hypertrophy is known to be the most common aetiology of this entity in childhood [2]. Main pathogenesis of this cardiovascular complication is suggested to be hypoventilation due to nasal and/or upper airway obstruction because increased PAP decreased to normal levels by relief of obstruction after adenotonsillectomy [25]. However, there has been no data showing whether there is any change in PAP of children with AR having significant nasal or upper airway obstruction during allergen exposure and therapy of AR changes PAP. In our study, children with AR, especially with PAR, had increased levels of PAP compared with their healthy matched controls was observed. More-
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
over, the increased PAP significantly decreased to normal levels after resolving nasal obstruction by treatment with nasal topical corticosteroids. All symptoms and cardiovascular complications related to adenotonsillar hypertrophy can be reversed by resolving upper respiratory obstruction after adenotonsillectomy [3,8]. Pharyngeal obstruction in this disorder has been related with increasing in PAP [5,7,25]. Since pharyngeal obstruction makes nasal airflow difficult, physiologic ventilation to the lungs is impaired [4]. On account of the fact that usual inspiration has to be supplied by nasal airflow, upper airway resistance is rised to increase nasal airflow and finally, it resulted in upper airway resistance syndrome [5]. If sufficiently qualified ventilation by nasal flow could not be supplied by this compensatory mechanisms, mandatory mouth-breathing or oral respiration has to be established [4,6]. However, mouth-breathing is not completely achieved during night-time due to pharyngeal muscule relaxation and retroposition of tongue while sleeping
25
[6]. Therefore, both of them may result in alveolar hypoventilation, hypoxia and hypercarbia while asleep [4,6,7,25]. This may lead to hypoxic pulmonar vasocontsriction and also increased PAP or pulmonary arterial hypertension if the disease persists for a long time [8,9]. Secreted vasoactive substances, such as endothelin-1, from endothelial cells and increased permeability to Ca+ + due to chronic hypoxia and hypercarbia in alveolar capillary ends are possibly responsible of hypoxic pulmonary vasoconstriction [8– 10]. In addition, in children with adenotonsillar hypertrophy, chronic nocturnal hypoxia and hypercarbia decrease sensitivity of respiratory center in central nervous system to peripheral stimuli and existing upper airway resistance syndrome result in OSA [11]. OSA and increased PAP are always reversible by the elimination of the cause, pharyngeal obstruction, using adenotonsillectomy [8,9,25]. In those children, Miman et al. showed that preoperative increased PAP decreased dramatically to normal level after
Fig. 1. Mean levels of systolic PAP of groups. PAP, pulmonary arterial pressure; T, whole study group; P, children with PAR; S, children with SAR; a, post-treatment levels; b, baseline; c, control group; *, c , &, +, significant difference between same symbols.
26
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
adenoidectomy and/or tonsillectomy by using Doppler echocardiography [25]. However, it is not clear whether other factors causing nasal or upper airway obstruction, such as AR, lead to increased PAP and elimination of these factors may resolve complication. The incidence of AR in childhood is 6– 15% in our country and increases as other allergic diseases [13]. The most potent agents for the treatment of AR, especially nasal obstruction, are nasal topical corticosteroids [21]. Children with chronic and significant nasal obstruction related to AR may develop mandatory mouth breathing, snoring and hyponasal speech, as observed in children with adenotonsillary hypertrophy [14,18]. Moreover Nicholas et al. reported that adults with symptomatic AR may develop OSAS [26]. In addition to the above mentioned classical symptoms, we observed an increase of PAP in children with symptomatic AR. According to our results, we may speculate that AR may cause upper airway resistance syndrome and increased PAP secondary to pulmonary arterial vasoconstriction with similar mechanisms in children having adenotonsillar hypertrophy. The fact that we observed higher PAP levels in children with PAR having longer lasting nasal obstruction compared with children with SAR is supporting our hypothesis. Moreover, dramatic decrease of PAP after cure of nasal obstruction by topical corticosteroids, further supports our idea. However, we could not find any relation between symptom scores and PAP levels. Therefore, we may suggest that the factors causing increased PAP are multiple and vary individually. In conclusion, our results suggest that children suffering from symptomatic AR have higher PAP levels compared with healthy controls. In children with serious nasal obstruction, the increase of PAP owing to upper airway resistance syndrome may be more evident. Increased PAP due to the upper airway obstruction in AR may be reversible by using nasal topical corticosteroids. Doppler echocardiography is a safe, non-invasive and reliable method for the evaluation of PAP in children with AR. Further investigations are necessary to clarify the clinical importance of increased PAP in children with AR during symptomatic period.
References [1] G.J. Redding, Pulmonary hypertenison and cor pulmonale in children, in: B.C. Hilman (Ed.), Pediatric Respiratory Diseases: Diagnosis and Treatment, Saunders, Philadelphia, 1993, pp. 335 – 353. [2] M.G. Lind, B.P. Lundell, Tonsillar hyperplasia in children. A cause of obstructive sleep apneas, CO retention and retarded growth, Arch. Otolaryngol. 108 (1982) 650 – 654. [3] E. Laurikainen, K. Aitasalo, M. Erkinjuntti, O. Wanne, Sleep apnea syndrome in children. Secondary to adenotonsillar hypertrophy?, Acta. Otolaryngol. (Suppl.) 492 (1992) 38 – 41. [4] W.P. Potsic, P.S. Pasquariello, C.C. Baranak, R.R. Marsh, L.M. Miller, Relief of upper airway obstruction by adenotonsillectomy, Otolaryngol. Head Neck Surg. 94 (1986) 476 – 480. [5] C. Guilleminault, R. Stoohs, A. Clerk, J. Simmons, M. Labanowski, From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness, Sleep 15 (1992) 513 – 516. [6] G.M. Grundfast, D.J. Wittich Jr, Adenotonsillar hypertrophy and upper airway obstruction in evolutionary perspective, Laryngoscope 92 (1982) 650 – 656. [7] N.A. Goldstein, J.C. Post, R.M. Rosenfeld, T.F. Campbell, Impact of tonsillectomy and adenoidectomy on child behavior, Arch. Otolaryngol. Head Neck Surg. 126 (2000) 494 – 498. [8] D.Y. Aji, A. Sarioglu, L. Sever, N. Arisoy, Pulmonary hypertension due to chronic upper airway obstruction: a clinical review and report of four cases, Turk. J. Pediatr. 33 (1991) 35 – 41. [9] A.M. Talaat, M.M. Nahhas, Cardiopulmonary changes secondary to adenotonsillitis, Arch. Otolaryngol. 109 (1983) 30 – 33. [10] D.W. Hay, Putative mediator role of endotelin-1 in asthma and other lung diseases, Clin. Exp. Pharmacol. Physiol. 26 (1999) 168 – 171. [11] A. Sanchez-Armengol, F. Capote-Gil, S. Cano-Gomez, R. Ayerbe-Garcia, F. Delgado-Moreno, J. CastiloGomez, Polysomnographic studies in children with adenotonsillar hypertrophy and suspected obstructive sleep apnea, Pediatr. Pulmonol. 22 (1996) 101 – 105. [12] E.F. Williams, P. Woo, R. Miller, R.M. Kellman, The effects of adenotonsillectomy on growth in young children, Otolaryngol. Head Neck Surg. 104 (1991) 509 – 516. [13] A.F. Kalyoncu, Z.T. Selc¸ uk, Y. Karakoca, A.S. Emri, L. C ¸ o¨ plu¨ , A.A. Sahin, Y.I. Baris, Prevalance of childhood asthma and allergic diseases in Ankara, Turkey, Allergy 49 (1994) 485 – 488. [14] B. Sibbald, E. Rink, Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history, Thorax 46 (1991) 859 – 901. [15] A.L. Wright, C.G. Holberg, F.D. Martinez, Epidemiology of physician diagnosed allergic rhinitis in childhood, Pediatrics 94 (1994) 895 – 901.
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27 [16] J.N. Baranuik, Pathogenesis of allergic rhinitis, J. Allergy Clin. Immunol. 99 (1997) 763 –772. [17] S.J. Wilson, L. Lau, P.H. Howarth, Inflammatory mediators in naturally occuring rhinitis, Clin. Exp. Allergy 28 (1998) 220 – 227. [18] N. Aberg, J. Sundel, B. Erikkson, B. Hesselmar, B. Aberg, Prevelance of allergic diseases in schoolchildren in relation to family history, upper respiratory tract infections and residental characteristics, Allergy 51 (1996) 232 – 237. [19] G.W. Canonica, G. Ciprandi, S. Buscaglia, G. Pesce, M. Bagnasco, Adhesion molecules of allergic inflammation: recent insights into their functional roles, Allergy 49 (1994) 135 – 141. [20] M. Anderson, R. Berglund, L. Greiff, et al., A comparison of budesonide nasal dry powder with fluticasone propionate aqueous nasal spray in patients with perennial allergic rhinitis, Rhinology 33 (1995) 18 –21.
.
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[21] J.M. Weiner, M.J. Abramson, R.M. Puy, Intranasal corticosteroids versus oral H1 receptor antagonsits in allergic rhinitis: systematic review of randomized controlled trial, Br. Med. J. 317 (1998) 1624 – 1629. [22] International Rhinitis Management Working Group. International Consensus Report on the Diagnosis and Management of Rhinitis. Allergy 1994; 49 (Suppl) 9: 5 – 34. [23] H. Feigenbaum, Echocardiography, Fifth ed., Lea & Febiger, Pennsylvania, 1994, pp. 181 – 215. [24] K.C. Sie, J.A. Perkins, W.R. Clarke, Acute right heart failure due to adenotonsillar hypertrophy, Int. J. Pediatr. Otolaryngol. 41 (1997) 53 – 58. [25] M.C. Miman, T. Kirazli, R. O8 zyu¨ rek, Doppler echocardiography in adenotonsillar hypertrophy, Int. J. Pediatr. Otolaryngol. 54 (2000) 21 – 26. [26] W.T. McNicholas, S. Tarlo, P. Cole, et al., Obstructive apneas during sleep in patients with seasonal allergic rhinitis, Am. Rev. Respir. Dis. 126 (1982) 625 – 628.
Doppler echocardiographic evaluation of pulmonary arterial pressure in children with allergic rhinitis Hasan Yu¨ksel *, S¸enol Cos¸kun, Ali Onag˘ Department of Pediatrics, Medical Faculty, Celal Bayar U8 ni6ersity, Manisa, Turkey Received 30 January 2001; received in revised form 23 April 2001; accepted 24 April 2001
Abstract In children, persistent upper airway obstruction may lead to increased pulmonary arterial pressure (PAP). Allergic rhinitis (AR) is one of the frequent cause of persisting upper airway obstruction by nasal blockage in childhood. Regular use of nasal topical corticosteroids are effective in reducing nasal blockage and obstruction. However, whether symptomatic children with AR have increased PAP and curative effect of topical steroids are not known. The aims of this study were to clarify whether children having active symptoms of AR have increased PAP and to investigate the curative effect of reducing nasal obstruction by topical corticosteroids. Twenty-three children, aged between 5 and 16, diagnosed as AR, consisted of 17 seasonal AR (SAR) and seven perennial AR (PAR), were included in the study. Nineteen age and sex matched healthy children were received as controls. PAP was measured by using Doppler echocardiography in all subjects and symptom scores of AR were recorded in rhinitis group. After first evaluation, nasal steroid, budesonid, was given to rhinitis group for three months. Mean systolic PAP was 33.4 93.1 for children with AR mmHg and 23.6 94.3 mmHg for the control group. The difference was statistically significant (PB 0.05). Mean systolic PAP of children with PAR was significantly higher than children with SAR (PB 0.05). In rhinitis group, mean PAP decreased significantly after relief of upper airway obstruction by nasal corticosteroid therapy to normal level of 24.9 93.6 mmHg (P B 0.05). Our results showed that children with AR may have significantly higher PAP than healthy subjects and decreased to normal levels after relieving nasal blockage by nasal corticosteroids. Nevertheless, Doppler echocardiography is a safe, non-invasive and practical tool for cardiac investigation of children with AR. Therefore, in symptomatic period, evaluation of PAP of children with AR by using Doppler echocardiography may be useful in the planning and following of their therapy. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Allergic-rhinitis; Children; Pulmonary-arterial-pressure
1. Introduction * Corresponding author. Present address: 244 Sokak No: 10/2 D: 14, 35040 Bornova-I: zmir, Turkey. Tel.: + 90-2323436968; fax: + 90-236-2370213. E-mail address: [email protected] (H. Yu¨ksel).
Persistent or chronic upper airway obstruction may lead to cardiovascular deterioration by increasing pulmonary arterial pressure (PAP) in childhood [1]. Adenotonsillar hypertrophy charac-
0165-5876/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 5 8 7 6 ( 0 1 ) 0 0 5 0 0 - 6
22
H. Yu¨ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
terized by nasal blockage, upper airway obstruction, mandatory mouth breathing and recurrent upper respiratory infection is known as the most common cause of increased PAP due to chronic upper airway obstruction in childhood [2]. It was demonstrated earlier that increased PAP and cor pulmonale in children with adenotonsillar hypertrophy could successfully be reversed after relief of upper airway obstruction by adenoidectomy [3,4]. Adenotonsillar hypertrophy results in nasopharyngeal obstruction and upper airway resistance syndrome [5]. Then compensation of insufficient nasal ventilation causes mandatory mouth breathing [4,6]. However, since mouth breathing does not provide sufficient air supply during night-time, insufficient inflation results in alveolar hypoventilation, hypoxemia and hypercarbia [6,7]. Therefore, upper airway obstruction may lead to hypoxic pulmonary vasoconstriction. Pulmonary arterial hypertension occurs as a result of vasopressor mediator release from pulmonary vascular bed and increased endothelial sensitivity to vasoconstrictor mediators owing to sustained upper airway obstruction [8– 10]. Nocturnal hypoxemia and hypercarbia may cause obstructive sleep apnea syndrome (OSA), snoring, hyponasal speech, nocturnal enuresis, obesity and growth retardation [6,11,12]. Allergic rhinitis (AR) is the most common allergic disease of upper respiratory tract and is characterized by IgE mediated allergic response to environmental allergens and immunocellular infiltration in nasal mucosa. Prevalence of AR among children is approximately 6– 15% and increasing gradually [13,14]. The most characteristic symptoms are nasal blockage related to nasal mucosal inflammation, sneezing, nasal itching and watery rhinorrhoea [15– 17]. According to the time of exposure, AR can be subdivided into seasonal (SAR), related to pollens, and perennial (PAR), related to house dust allergens and animal dander [16]. In children with AR, mandatory mouth breathing, snoring, hyponasal speech and occasionally OSA may develop due to nasal blockage and upper airway obstruction as occur in subjects with adenotonsillar hypertrophy [14,18]. However, possible upper airway resistance syndrome and increased PAP due to AR has not
been studied earlier. The main cause of upper airway resistance syndrome and nasal blockage in AR is eosinophilic inflammation of nasal mucosa and edema due to IgE mediated persistent allergic reaction [19]. Thus, rational therapy of nasal obstruction in this disorder is topical anti-inflammatory therapy [20]. The most potent nasal topical anti-inflammatory agents are topical corticosteroids such as budesonide [21]. Also, whether there is any change in PAP after reducing nasal obstruction by using nasal corticosteroids has not been studied earlier. In this study, the children who were affected by upper respiratory obstruction due to AR and the effects of nasal corticosteroids on those were evaluated by clinical and laboratory investigations. The aims were to clarify whether children with active symptoms of AR have increased PAP and to demonstrate whether there is any beneficial effect of nasal topical corticosteroids on this possible complication. 2. Materials and methods
2.1. Study group Twenty-four children diagnosed as AR and followed-up in our Paediatric Allergy outpatientclinic were enrolled into the study. They were composed of 17 subjects with SAR and seven subjects with PAR according to their history, clinical and laboratory criteria. The definition of AR was made by using International Consensus Statement on the management of AR [22]. Therefore, subjects with AR were diagnosed as those individuals with a characteristic history of perennial or seasonal symptoms of AR (rhinorrhoea, sneezing, nasal obstruction and pruritis) and who also had skin sensitization to perennial or seasonal allergens. All our subjects had seasonal or perennial symptom history of AR for at least 2 years. Also, they had positive family history of atopy, high serum IgE levels (Diagnostic Automation Inc., CA, USA), positive skin-prick tests responses (] 3 mm wheal diameter) to pollen extracts of grass mix, as seasonal allergens, or Dermatophagoides Pteronyssinus and Farinea, as perennial allergens (Allergopharma JGK, Rein-
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
bek, Germany). Exclusion criteria included presence of other causes of nasal obstruction such as nasal polyps and rhinosinusitis. We also excluded children, who were using nasal topical or systemic corticosteroids, antihistamines or other anti-allergic drugs within earlier 2 months. To compare PAP values, 19 non-atopic, healthy, sex and age matched children were included as a control group. Table 1 shows demographic and clinical characteristics of study and control groups.
3. Study design After the inclusion and exclusion criteria were examined, baseline symptom score was noted and PAP was measured by using Doppler echocardiography. On this visit, families and children were instructed to administer twice a day nasal corticosteroid, budesonide (Rhinocort Aqua Nasal Spray, AstraZeneca Co., USA), by using a dose of 200 mg per day (one puff in each nostril), in the morning and evening for 8 weeks. At the end of the study, their symptoms scores and PAP values were evaluated and noted. All subjects were warned to admit to the clinic, when there was any exacerbation in their symptoms.
3.1. Symptom scoring To score nasal obstruction symptoms of children with AR, parents and subjects were asked by
23
using standard criteria which are presented in Table 2. The criteria included upper airway obstruction symptoms such as nasal blockage, snoring, mouth-breathing during sleep and daytime, hyponasal voice. Scores of symptoms were between ‘0’ and ‘5’ points.
3.2. Doppler echocardiography After routine cardiovascular examination, they were also examined by using Doppler echocardiography to obtain PAP values. Doppler echocardiography was performed using 2-D Colored-Doppler Echocardiography (Image Point, Hewlett-Packard Co, California, USA) applied with 2.5 MHz transducer. Systolic PAP was obtained from maximum pressure gradient between right ventricle and right atrium. It was determined with the Bernoulli equation by using the peak velocity of the tricuspid regurgitant jet. Peak velocity of tricuspid regurgitant jet was recorded by continuous wave Doppler echocardiography. Four-chamber view of heart was used for this echocardiographic examination. Color Doppler imaging was used for determination of the correct angle of regurgitant jet. To determine right atrium pressure, inspiratory collapse of inferior vena cava was used. When the diameter of inferior vena cava decreased more than 50% during inspiration, right atrium pressure was accepted as 10 mmHg. However, if this decreasing was less than 50%, right atrium pressure was
Table 1 Demographic and clinical characteristics of subjects Characteristics
Allergic rhinitis (n = 24)
Controls (n = 19)
P
Sex (F/M) SAR (n =17)a PAR (n = 7)b 5/2 Age (year) Symptom duration (year) Positive family history of atopy (%) High serum IgE Positive SPTc
9/5 10/9 5–16 (10.393.5) 2–6 (2.99 1.7) 22 (92) All All
\0.05 6–14 (9.8 92.7) – – –
\0.05 – – – –
a
Seasonal AR. Perennial AR. c Skin prick test. b
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27
24
Table 2 Scoring nasal obstruction symptoms of children with allergic rhinitis Symptom ¡ score
0
1
2
3
4
5
Nasal blockage Mouth breathing Hyponasal voice Snoring Restless sleeping
No No No No No
Rarely Rarely Rarely Almost never Rarely
Mild Mild intermittent Occasionally Rarely Occasionally
Moderate Moderate intermittent Intermittent Intermittent Rather frequently
Severe Frequently Frequently Frequently Frequently
Very serious Always Always Every day Every day
accepted as increased. PAP was calculated by using pressure gradient as mentioned above and right atrium pressure as described earlier [23].
3.3. Statistics PAP values of study and control groups were analyzed by using unequal variance t-test. Preand post treatment symptom scores and PAP values of study group were compared by using equal variance t-test. P-value was accepted as significant less than 0.05.
4. Results
children with PAR had higher mean systolic PAP than children with SAR. Values were 35.29 3.9 and 31.59 2.7 mmHg, respectively, (P B0.05). Mean systolic PAP of study group significantly decreased to the level of 24.99 3.6 mmHg at the end of study (PB 0.05). Also, both PAP values of children with PAR and SAR were significantly decreased by nasal topical therapy. Post treatment PAP levels of both patients were 26.69 3.7 and 24.39 2.9 mmHg, respectively. Fig. 1 shows mean levels of systolic PAP of groups. No significantly correlation were obtained between systolic PAP levels and symptom scores (rB 0.25). All subjects had no other additional echocardiographic pathology.
4.1. Demographic and clinic characteristics 5. Discussion The mean age of the study group was 10.39 3.5 years. There were no significant differences between the age and sex characteristics of the study and control groups (Table 1). Mean duration of symptoms was more than 2 years in study group and a high percentage of these had positive family history of atopy (Table 1). Mean pre-treatment symptom score of these children was 3.69 1.4 per patient and significantly decreased to 1.19 0.5 per patient at the end of eight weeks of nasal topical corticosteroid therapy (P B0.05).
4.2. Pulmonary arterial pressure Mean pre-treatment systolic PAP of study group with 33.49 3.1 mmHg was significantly higher than in healthy control which was 23.69 4.3 mmHg (P B 0.05). When compared with mean systolic PAP of subjects with PAR and SAR, the
Persistent or chronic upper airway obstruction are believed to lead to increased PAP, pulmonary hypertension, cor pulmonale and moreover acute right heart failure [1,24]. Adenotonsillar hypertrophy is known to be the most common aetiology of this entity in childhood [2]. Main pathogenesis of this cardiovascular complication is suggested to be hypoventilation due to nasal and/or upper airway obstruction because increased PAP decreased to normal levels by relief of obstruction after adenotonsillectomy [25]. However, there has been no data showing whether there is any change in PAP of children with AR having significant nasal or upper airway obstruction during allergen exposure and therapy of AR changes PAP. In our study, children with AR, especially with PAR, had increased levels of PAP compared with their healthy matched controls was observed. More-
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over, the increased PAP significantly decreased to normal levels after resolving nasal obstruction by treatment with nasal topical corticosteroids. All symptoms and cardiovascular complications related to adenotonsillar hypertrophy can be reversed by resolving upper respiratory obstruction after adenotonsillectomy [3,8]. Pharyngeal obstruction in this disorder has been related with increasing in PAP [5,7,25]. Since pharyngeal obstruction makes nasal airflow difficult, physiologic ventilation to the lungs is impaired [4]. On account of the fact that usual inspiration has to be supplied by nasal airflow, upper airway resistance is rised to increase nasal airflow and finally, it resulted in upper airway resistance syndrome [5]. If sufficiently qualified ventilation by nasal flow could not be supplied by this compensatory mechanisms, mandatory mouth-breathing or oral respiration has to be established [4,6]. However, mouth-breathing is not completely achieved during night-time due to pharyngeal muscule relaxation and retroposition of tongue while sleeping
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[6]. Therefore, both of them may result in alveolar hypoventilation, hypoxia and hypercarbia while asleep [4,6,7,25]. This may lead to hypoxic pulmonar vasocontsriction and also increased PAP or pulmonary arterial hypertension if the disease persists for a long time [8,9]. Secreted vasoactive substances, such as endothelin-1, from endothelial cells and increased permeability to Ca+ + due to chronic hypoxia and hypercarbia in alveolar capillary ends are possibly responsible of hypoxic pulmonary vasoconstriction [8– 10]. In addition, in children with adenotonsillar hypertrophy, chronic nocturnal hypoxia and hypercarbia decrease sensitivity of respiratory center in central nervous system to peripheral stimuli and existing upper airway resistance syndrome result in OSA [11]. OSA and increased PAP are always reversible by the elimination of the cause, pharyngeal obstruction, using adenotonsillectomy [8,9,25]. In those children, Miman et al. showed that preoperative increased PAP decreased dramatically to normal level after
Fig. 1. Mean levels of systolic PAP of groups. PAP, pulmonary arterial pressure; T, whole study group; P, children with PAR; S, children with SAR; a, post-treatment levels; b, baseline; c, control group; *, c , &, +, significant difference between same symbols.
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adenoidectomy and/or tonsillectomy by using Doppler echocardiography [25]. However, it is not clear whether other factors causing nasal or upper airway obstruction, such as AR, lead to increased PAP and elimination of these factors may resolve complication. The incidence of AR in childhood is 6– 15% in our country and increases as other allergic diseases [13]. The most potent agents for the treatment of AR, especially nasal obstruction, are nasal topical corticosteroids [21]. Children with chronic and significant nasal obstruction related to AR may develop mandatory mouth breathing, snoring and hyponasal speech, as observed in children with adenotonsillary hypertrophy [14,18]. Moreover Nicholas et al. reported that adults with symptomatic AR may develop OSAS [26]. In addition to the above mentioned classical symptoms, we observed an increase of PAP in children with symptomatic AR. According to our results, we may speculate that AR may cause upper airway resistance syndrome and increased PAP secondary to pulmonary arterial vasoconstriction with similar mechanisms in children having adenotonsillar hypertrophy. The fact that we observed higher PAP levels in children with PAR having longer lasting nasal obstruction compared with children with SAR is supporting our hypothesis. Moreover, dramatic decrease of PAP after cure of nasal obstruction by topical corticosteroids, further supports our idea. However, we could not find any relation between symptom scores and PAP levels. Therefore, we may suggest that the factors causing increased PAP are multiple and vary individually. In conclusion, our results suggest that children suffering from symptomatic AR have higher PAP levels compared with healthy controls. In children with serious nasal obstruction, the increase of PAP owing to upper airway resistance syndrome may be more evident. Increased PAP due to the upper airway obstruction in AR may be reversible by using nasal topical corticosteroids. Doppler echocardiography is a safe, non-invasive and reliable method for the evaluation of PAP in children with AR. Further investigations are necessary to clarify the clinical importance of increased PAP in children with AR during symptomatic period.
References [1] G.J. Redding, Pulmonary hypertenison and cor pulmonale in children, in: B.C. Hilman (Ed.), Pediatric Respiratory Diseases: Diagnosis and Treatment, Saunders, Philadelphia, 1993, pp. 335 – 353. [2] M.G. Lind, B.P. Lundell, Tonsillar hyperplasia in children. A cause of obstructive sleep apneas, CO retention and retarded growth, Arch. Otolaryngol. 108 (1982) 650 – 654. [3] E. Laurikainen, K. Aitasalo, M. Erkinjuntti, O. Wanne, Sleep apnea syndrome in children. Secondary to adenotonsillar hypertrophy?, Acta. Otolaryngol. (Suppl.) 492 (1992) 38 – 41. [4] W.P. Potsic, P.S. Pasquariello, C.C. Baranak, R.R. Marsh, L.M. Miller, Relief of upper airway obstruction by adenotonsillectomy, Otolaryngol. Head Neck Surg. 94 (1986) 476 – 480. [5] C. Guilleminault, R. Stoohs, A. Clerk, J. Simmons, M. Labanowski, From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness, Sleep 15 (1992) 513 – 516. [6] G.M. Grundfast, D.J. Wittich Jr, Adenotonsillar hypertrophy and upper airway obstruction in evolutionary perspective, Laryngoscope 92 (1982) 650 – 656. [7] N.A. Goldstein, J.C. Post, R.M. Rosenfeld, T.F. Campbell, Impact of tonsillectomy and adenoidectomy on child behavior, Arch. Otolaryngol. Head Neck Surg. 126 (2000) 494 – 498. [8] D.Y. Aji, A. Sarioglu, L. Sever, N. Arisoy, Pulmonary hypertension due to chronic upper airway obstruction: a clinical review and report of four cases, Turk. J. Pediatr. 33 (1991) 35 – 41. [9] A.M. Talaat, M.M. Nahhas, Cardiopulmonary changes secondary to adenotonsillitis, Arch. Otolaryngol. 109 (1983) 30 – 33. [10] D.W. Hay, Putative mediator role of endotelin-1 in asthma and other lung diseases, Clin. Exp. Pharmacol. Physiol. 26 (1999) 168 – 171. [11] A. Sanchez-Armengol, F. Capote-Gil, S. Cano-Gomez, R. Ayerbe-Garcia, F. Delgado-Moreno, J. CastiloGomez, Polysomnographic studies in children with adenotonsillar hypertrophy and suspected obstructive sleep apnea, Pediatr. Pulmonol. 22 (1996) 101 – 105. [12] E.F. Williams, P. Woo, R. Miller, R.M. Kellman, The effects of adenotonsillectomy on growth in young children, Otolaryngol. Head Neck Surg. 104 (1991) 509 – 516. [13] A.F. Kalyoncu, Z.T. Selc¸ uk, Y. Karakoca, A.S. Emri, L. C ¸ o¨ plu¨ , A.A. Sahin, Y.I. Baris, Prevalance of childhood asthma and allergic diseases in Ankara, Turkey, Allergy 49 (1994) 485 – 488. [14] B. Sibbald, E. Rink, Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history, Thorax 46 (1991) 859 – 901. [15] A.L. Wright, C.G. Holberg, F.D. Martinez, Epidemiology of physician diagnosed allergic rhinitis in childhood, Pediatrics 94 (1994) 895 – 901.
H. Yu¨ ksel et al. / Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 21–27 [16] J.N. Baranuik, Pathogenesis of allergic rhinitis, J. Allergy Clin. Immunol. 99 (1997) 763 –772. [17] S.J. Wilson, L. Lau, P.H. Howarth, Inflammatory mediators in naturally occuring rhinitis, Clin. Exp. Allergy 28 (1998) 220 – 227. [18] N. Aberg, J. Sundel, B. Erikkson, B. Hesselmar, B. Aberg, Prevelance of allergic diseases in schoolchildren in relation to family history, upper respiratory tract infections and residental characteristics, Allergy 51 (1996) 232 – 237. [19] G.W. Canonica, G. Ciprandi, S. Buscaglia, G. Pesce, M. Bagnasco, Adhesion molecules of allergic inflammation: recent insights into their functional roles, Allergy 49 (1994) 135 – 141. [20] M. Anderson, R. Berglund, L. Greiff, et al., A comparison of budesonide nasal dry powder with fluticasone propionate aqueous nasal spray in patients with perennial allergic rhinitis, Rhinology 33 (1995) 18 –21.
.
27
[21] J.M. Weiner, M.J. Abramson, R.M. Puy, Intranasal corticosteroids versus oral H1 receptor antagonsits in allergic rhinitis: systematic review of randomized controlled trial, Br. Med. J. 317 (1998) 1624 – 1629. [22] International Rhinitis Management Working Group. International Consensus Report on the Diagnosis and Management of Rhinitis. Allergy 1994; 49 (Suppl) 9: 5 – 34. [23] H. Feigenbaum, Echocardiography, Fifth ed., Lea & Febiger, Pennsylvania, 1994, pp. 181 – 215. [24] K.C. Sie, J.A. Perkins, W.R. Clarke, Acute right heart failure due to adenotonsillar hypertrophy, Int. J. Pediatr. Otolaryngol. 41 (1997) 53 – 58. [25] M.C. Miman, T. Kirazli, R. O8 zyu¨ rek, Doppler echocardiography in adenotonsillar hypertrophy, Int. J. Pediatr. Otolaryngol. 54 (2000) 21 – 26. [26] W.T. McNicholas, S. Tarlo, P. Cole, et al., Obstructive apneas during sleep in patients with seasonal allergic rhinitis, Am. Rev. Respir. Dis. 126 (1982) 625 – 628.