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Improvement of Bronchial Hyperresponsiveness in Asthmatic Children Treated for Concomitant Sinusitis
Improvement of bronchial hyperresponsiveness in asthmatic children treated for concomitant sinusitis Carlos A A Oliveira, MD*; Dirceu Sole´, MD*; Charles K Naspitz, MD*; and Gary S Rachelefsky, MD†
Background: There appears to be an association between sinusitis and asthma. The effect on bronchial hyperresponsiveness of clinical therapy for sinusitis in children may help to decipher whether sinusitis and asthma are independent manifestations of the same disease. Objective: To evaluate the effect of clinical treatment for sinusitis in patients with rhinitis and/or asthma on symptoms and on bronchial hyperresponsiveness to methacholine. Methods: Open label, randomized, non-treatment control in a teaching hospital in Sa˜o Paulo, Brazil. Forty-six atopic and 20 normal children were studied. The atopic children consisted of 18 with allergic rhinitis (12 without sinusitis and 6 with sinusitis), and 28 children with rhinitis with asthma (13 with normal sinus radiographs and 15 with complete opacification of the maxillary sinuses). Methacholine PC20 was determined before and 30 days after treatment with nasal saline, sulfamethoxazole-trimethoprim, antihistamine/decongestant, and five days of prednisone. Sinus radiographs were also repeated. Results: The only patients with increase in methacholine PC20 were patients with rhinitis and asthma with opacified maxillary sinuses at entry and who at 30 days had normal sinus radiographs (P ⬍ .05). Conclusion: In this study, children with allergic rhinitis and sinusitis with asthma improved their bronchial hyperresponsiveness to methacholine and decreased their symptoms with appropriate response of their sinuses to clinical therapy. Ann Allergy Asthma Immunol 1997;79:70– 4.
INTRODUCTION For many years the association between sinusitis and asthma has been described. The first studies relating upper airways (nose, nasopharynx, and paranasal sinuses) and bronchi began with Kratchmer in 1870.1 He showed that chemical irritation of the nasal mucosa in cats and rabbits resulted in bronchoconstriction. Electrical and mechanical stimulation of the nasal
* Division of Allergy, Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of Sa˜o Paulo Escola Paulista de Medicina, Brazil. † Allergy Research Foundation, Los Angeles, California, USA. Received for publication August 22, 1996. Accepted for publication in revised form January 29, 1997.
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mucosa resulted also in reflex bronchoconstriction.2 In the beginning of this century, several studies described the incidence of sinusitis in asthmatic patients varying between 12%3 and 90%.4 Later it was believed that sinusitis reflected only broader changes of the respiratory tract other than the indirect effect of the worsening of lower airway function; thus, until the 1970s little was published about the association of sinusitis with asthma. In 1984, Rachelefsky et al5 observed that children with asthma showed remarkable improvement of lower airway symptoms and pulmonary function after diagnosis and concomitant treatment of sinusitis. Other studies showed the same results whether the sinus disease was treated clinically6 or
surgically.7,8 There are no doubts that sinusitis and asthma do coexist. The key point is to know whether sinusitis and asthma are independent manifestations of the same disease or whether sinusitis by itself can trigger or aggravate asthma. More recently, evidence of increased lower airway responsiveness associated with sinusitis has been found.9,10 In this study, we evaluated nonspecific bronchial hyperresponsiveness (BHR) by methacholine challenge in children with perennial allergic rhinitis alone or associated with asthma and/or sinusitis. After clinical treatment of those children with sinusitis, the BHR was again determined to evaluate whether or not such intervention would alter BHR. PATIENTS AND METHODS Forty-six atopic children and twenty normal children were included in this study. (Table 1) The atopic patients were selected from 152 children with rhinitis and/or asthma, and in all of them radiographs of the paranasal sinuses were obtained. The radiographs were obtained with the patient in orthostatic position, in three views: frontonasal (Caldwell), nasomental (Waters), and lateral. Inclusion criteria for the study were normal radiographs without nasal and/or postnasal purulent secretions, and those with complete opacification of one or both maxillary sinuses (lateral), with or without nasal and/or postnasal purulent secretions. Patients were included in the study if they had either a normal radiograph or complete opacification of one or both maxillary sinuses.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
The group of atopic patients consisted of 18 children with perennial allergic rhinitis, 12/18 with normal radiographs and 6/18 with complete opacification of the maxillary sinus; and of 28 children with rhinitis associated with asthma, 13/28 with normal radiographs and 15/28 with complete opacification of the maxillary sinuses. All patients had standardized histories obtained5 to elicit symptoms of rhinitis and sinusitis. All patients with rhinitis had had continuous symptoms for at least 6 months (nasal obstruction, nasal pruritus, sneezing, and coryza). After physical examination, they showed at least four of the following signs: dark circles under the eyes, Dennie’s lines, nasal transverse groove, oral respiration, V shaped palate, dental malocclusion, hypertrophy of the lower nasal conchae, and colorless or “bluish” nasal mucosa. In the group of children with rhinitis associated with asthma (n ⫽ 28), the asthma was classified according to severity as mild, moderate, and severe.11 All 46 patients demonstrated positive skin prick tests (⬎3 mm wheal diameter to Dermatophagoides pteronyssinus extract—30,000 allergy units per mL, Dome/Hollister–Stier, Division of Miles Inc); this group was the atopic group. Appropriate positive control skin tests with histamine and negative control tests with saline were also applied. The methacholine PC20 was determined in the 46 patients using a provocative concentration of methacholine causing a 20% fall in FEV1.12,13 Forced expiratory volume in one second (FEV1) was obtained and expressed as a percentage of the predicted.14 Subjects were clinically reevaluated after 15 and 30 days of treatment. Repeat radiographs and methacholine challenges were obtained after 30 days of treatment. Normal children had no previous clinical history of chronic rhinitis or asthma, and had no family and personal history of atopic diseases. Skin prick tests with Dermatophagoides pteronyssinus were negative. For ethi-
VOLUME 79, JULY, 1997
cal reasons, radiographs of the paranasal sinuses were not taken. Bronchoprovocation was performed only at entry. All subjects and parents provided statements of informed consent, and the study was approved by the Ethical Committee of UNIFESP-EPM. Clinical treatment Children with normal radiographs were treated only with intranasal saline for 30 days.15 Children with opacification of the maxillary sinuses were treated with our standard approach, which includes (a) intranasal saline; (b) prednisone (1 to 2 mg/kg/once a day/5 days); (c) sulfamethoxazole and trimethoprim (40 mg/kg/day of sulfamethoxazole and 8 mg/kg/day of trimethoprim, q 12h for 21 days); and (d) an antihistamine (azatadine) 1 to 2 mg and a systemic decongestant (pseudoephedrine) 30 to 60 mg, thrice/day for 21 days. All medications were administered concurrently. Thirty days after treatment, all study children were submitted to a new radiograph in orthostatic position: frontonasal (Caldwell) and nasomental (Waters). Again, they were classified according to absence or presence of opacification of the maxillary sinuses. The following groups were obtained: group 1 was normal children (n ⫽ 20); group 2, children with perennial allergic rhinitis with normal radiographs before and after treatment with intranasal saline (n ⫽ 12); group 3, children with perennial allergic rhinitis with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 6); group 4, children with perennial allergic rhinitis and asthma with normal radiographs before and af-
ter treatment with intranasal saline (n ⫽ 13); group 5, children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 8); and group 6, children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses before and after clinical treatment (n ⫽ 7). The following tests were used for analysis of the results: Wilcoxon,16 to compare FEV1 and PC20 FEV1 methacholine before and after 30 days of treatment for each group, each patient acting as his own control; KruskalWallis’ variance analysis by ranks16 supplemented by the multiple comparison test17 to evaluate differences for all the groups before treatment with regard to FEV1, PC20, FEV1 methacholine, and age; and one criterion variance analysis,18 supplemented by the Scheffe´ contrast test,18 to evaluate differences with regard weight and height for all the groups. Differences were considered significant if a P value of less than .05 was obtained. RESULTS Group 1 comprised normal children: 7 girls and 13 boys with ages ranging from 7 years to 13 years and 2 months. Group 2 comprised 4 girls and 8 boys (ages ranging) from 7 years and 8 months to 14 years and 10 months). Duration of rhinitis varied from 1 to 12 years. Only one patient reported nocturnal cough that disappeared after treatment (Table 2). Group 3 comprised six children, 2 girls (ages ranging from 9 years and 6 months to 14 years and 3 months), all with rhinitis. Upon entry into study
Table 1. Normal Children (group 1) and Atopic Children (groups 2,3,4,5, and 6) in Relation to Average Age (years/months), Weight (kg), and Height (cm)
Age Weight Height*
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 12)
Group 3 (n ⴝ 6)
Group 4 (n ⴝ 13)
Group 5 (n ⴝ 8)
Group 6 (n ⴝ 7)
10/2 35.1 138.0
11/7 36.7 145.5
11/0 41.0 145.6
10/2 33.8 135.5
9/9 32.5 135.4
9/9 29.4 131.6
Kruskal Wallis—significant difference: group 6 ⬍ groups 2 and 3, * P ⬍ .05, and groups 1,2,3,4,5, and 6 —see text.
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50% of the children complained of headache and 75% of nocturnal cough. Purulent rhinorrhea was observed in 50% and 75% had purulent postnasal drip. All symptoms and signs disappeared after treatment, and radiographs of the maxillary sinuses became normal (Table 2). Group 4 comprised children with perennial allergic rhinitis associated with asthma, 4 girls and 9 boys (ages from 7 years and 5 months to 13 years and 10 months). Duration of rhinitis varied from 1 to 12 years, and asthma from 1 to 9 years: 3 were mild and 10 were moderate. Upon admission, nocturnal cough was the only symptom reported by 23.1% patients. After treatment, nocturnal cough persisted for only one of them. Purulent secretions were not observed upon admission (Table 2). Group 5 comprised eight children with perennial allergic rhinitis associated with asthma, 7 males (ages from 8 years to 13 years and 8 months). Duration of rhinitis varied from 2 to 12 years and of asthma from 4 to 12 years. According to the severity of asthma, 6 had mild, 1 moderate, and 1 severe. Headache was reported by 25% and nocturnal cough by 75% of patients upon admission. Half of them presented purulent coryza and purulent postnasal drip. All symptoms and signs were normal after treatment (Table 2). Group 6 comprised seven children with perennial allergic rhinitis associated with asthma, 6 males (ages from 7 years and 4 months to 11 years and 7 months). Duration of rhinitis varied from 2 to 10 years and of asthma from
5 years to 11 years 3 months. Three patients were affected by mild asthma, 2 by moderate asthma, and 2 by severe asthma. All of them had nocturnal cough, and 57% complained of headache. Purulent coryza was observed in 42.8% and purulent postnasal drip in 71.4%. Nocturnal cough after treatment disappeared in two patients only. Headache, purulent coryza, and purulent postnasal drip was observed in three different patients (Table 2). All groups were similar for age and weight. In relation to height, children of group 6 were of medium height (131.6 cm), significantly shorter than those of the groups 2 (145.5 cm) and 3 (145.6 cm) (Table 1). At admission, significantly lower values of FEV1 were observed in group 6 (75.6%), when compared with group 1 (96%). There were no significant differences between the groups of atopic children (Table 3). There were no differences between FEV1 values before and after treatment. Values of PC20 FEV1 methacholine determined before and 30 days after beginning of treatment for all groups are shown in Table 3 and Figure 1. Average basal value for the controls was 21.08 mg/mL; for those with rhinitis (groups 2 and 3) values were lower (15.08 and 10.70 mg/mL, respectively), and the lowest values (0.88; 0.76 and 2.91 mg/mL, respectively) were observed for those with perennial allergic rhinitis associated with asthma (groups 4, 5, and 6). PC20 FEV1 of methacholine of 4 mg/mL is the cutoff value for asthma.12 The comparison of PC20 FEV1 methacholine
Table 2. Clinical Symptoms and Signs of the Atopic Children (groups 2,3,4,5, and 6) Evaluated on Day Zero (0) and After 30 Days of Treatment (30)
Days
*Nocturnal cough *Headache *Purulent coryza *Purulent postnasal drip
Group 2 (n ⴝ 12)
Group 3 (n ⴝ 6)
Group 4 (n ⴝ 13)
Group 5 (n ⴝ 8)
Group 6 (n ⴝ 7)
0
30
0
30
0
30
0
30
0
30
1 0 0 0
0 0 0 0
4 3 3 4
0 0 0 0
3 0 0 0
1 0 0 0
6 2 4 4
0 0 0 0
7 4 3 5
5 1 1 1
* Number of patients with symptoms/signs: Groups 2,3,4,5 and 6 —see text.
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values upon admission (day 0) showed that the group 1 values were significantly higher than those of groups 4, 5, and 6. The group 2 values were significantly higher than those of groups 4 and 5 (Table 3 and Fig 1). PC20 FEV1 methacholine mean values from patients belonging to the allergic groups obtained after treatment showed a slight decrease for patients of groups 2 (10.83 mg/mL) and 3 (8.14 mg/mL). For patients of groups 4, 5 and 6, the mean values observed were 0.67 mg/ mL, 2.57 mg/mL, and 2.97 mg/mL, respectively. After treatment in the atopic patients, only group 5 showed a significant increase in PC20 FEV1 of methacholine: 0.76 to 2.57 mg/mL (Table 3 and Fig 1). DISCUSSION The main objectives of the clinical treatment of sinusitis are quick sterilization of the secretions and the re-establishment of ventilation, and drainage of the paranasal sinuses content.19,20 Radiologic changes of the paranasal sinuses in children with allergic rhinitis and/or asthma are observed frequently.21,22 In children with complete opacification of the maxillary sinuses or an air-fluid level, the recovery of bacteria in high counts from sinus aspirates would suggest that appropriate antimicrobial treatment of the sinus infection is important.23–25 Considering that Streptococcus pneumoniae was the main bacterial agent isolated in children with sinusitis in Brazil,25 the low socioeconomic level of the population studied and the easy administration of the drug, we used the combination sulfamethoxazole and trimethoprim to treat these patients for 21 days.19,20,26,27 Our atopic patients performed nasal hygiene with saline solution according to Mygind.15 Children with complete opacification of the maxillary sinuses, were also treated with prednisone, sulfamethoxazole and trimethoprim combination, antihistamine and systemic decongestant. Though there are few scientific data to reinforce the addition of other pharmacologic agents to the
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 3. Normal Children (group 1) and Atopic Children (groups 2,3,4,5, and 6), According to FEV1 (average, % predicted) and PC20 FEV1 of Methacholine Values (average, mg/mL) on Day Zero (0) and After 30 Days of Treatment (30)
FEV1 0 30 PC20 FEV1 0 30
Group 1
Group 2
Group 3
96.0 –
95.2 92.7
94.7 95.7
21.08 –
15.08 10.83
10.70 8.14
Group 4 87.3 83.3
0.88* 0.67
Group 5 83.9 88.5
0.76* 2.57†
Group 6 75.6* 82.1
2.91* 2.97
Kruskal Wallis day 0 (groups 1 ⫻ 2 ⫻ 3 ⫻ 4 ⫻ 5 ⫻ 6) FEV1 day 0 — group 1 ⬎ group 6, * P ⬍ .05 PC20 FEV1 day 0 — group 1 ⬎ groups 4,5 and 6 group 2 ⬎ groups 4 and 5, * P ⬍ .05 Wilcoxon (day 0 ⫻ day 30) FEV1, no significant differences PC20 FEV1— group 5: Day 0 ⬍ Day 30, † P ⬍ .05 Groups 1,2,3,4,5 and 6, see text
Figure 1. Normal children (group 1) and atopic children (groups 2,3,4,5, and 6), according to methacholine PC20 FEV1 (mean, mg/mL) on day zero (0) and after 30 days of treatment (30). Kruskal Wallis day 0 (groups 1⫻2⫻3⫻4⫻5⫻6). Group 1 ⬎ groups 4, 5, and 6. Group 2 ⬎ groups 4 and 5 ⫹ P ⬍ .05 Wilcoxon day 0 ⫻ day 30 Group 5: day 0 ⬍ day 30 *P ⬍ .05 Groups: 1 ⫽ normal children (n ⫽ 20), 2 ⫽ children with perennial allergic rhinitis with normal radiographs before and after treatment with intranasal saline (n ⫽ 12), 3 ⫽ children with perennial allergic rhinitis with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 6), 4 ⫽ children with perennial allergic rhinitis and asthma with normal radiographs before and after treatment with intranasal saline (n ⫽ 13), 5 ⫽ children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 8) and, 6 ⫽ children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses before and after clinical treatment (n ⫽ 7).
proper antimicrobial therapy, there are enough theoretical and practical reasons to do it.19 In several conditions with underlying inflammatory processes corticosteroids have demonstrated efficacy.19,28 The probable beneficial effects of alpha-adrenergic agents include edema reduction of the
VOLUME 79, JULY, 1997
nasal mucosa and decrease in the nasal resistance.29 We used antihistaminedecongestant combinations in our patients because they all presented with underlying atopic disease; nasal steroids were not used because of cost. Clinical data reported by the patients are shown in Table 2. There were sev-
eral prerequisites for admission to the study. Normal children and those with normal radiology of the maxillary sinuses (groups 2 and 4) were preselected. They were not admitted if purulent secretions were observed. There were no significant differences among the six groups studied relating to age and weight; however, the average height of the patients in group 6 (131.6 cm) was significantly shorter than that of groups 2 (145.5 cm) and 3 (145.6 cm) (Table 1). The main characteristics of group 6 were symptoms and signs of bacterial infection of the upper airways, frequently followed by aggravation of asthma. In addition, this group included two children with severe asthma and two with moderate asthma. Methacholine responsiveness is observed in asthmatic patients30,31 and many patients with allergic rhinitis. We observed higher values for PC20 FEV1 methacholine for normals, intermediate for pure rhinitics and lower when there was association with asthma (Table 3 and Fig 1). These data are similar to those observed by others.30,31 All asthmatic patients had low values of methacholine PC20 FEV1, regardless of the radiographic findings. Because of this, no relation between infection and BHR could be established. After 30 days of treatment, only in patients of group 5 was there a significant increase in the methacholine PC20 FEV1 values. In asthmatic patients, infection/inflammation in the maxillary sinuses may contribute to heightened bronchial hyperresponsiveness and appropriate clinical treatment of the sinusitis is important. This might be true only for asthmatic patients, since there were no changes in the BHR of rhinitic patients with sinusitis but without asthma (group 3). We recommend that the presence of sinusitis be considered in children with asthma who (1) have severe asthma, (2) do not respond to appropriate therapy, (3) have no obvious causes for their asthma, and (4) have associated significant upper airway symptoms. The presence of complete opacifica-
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tion of one or more maxillary sinuses, justifies aggressive pharmacologic intervention for sinusitis, resulting in improvement in symptoms and BHR.
11.
REFERENCES 1. Kratchmer I, cited by Allen W. Effect on respiration, blood pressure, and carotid pulse of various inhaled and insufflated vapors when stimulating one cranial nerve and various combinations of cranial nerves. Am J Physiol 1928;87:319 –25. 2. Dixon WE, Brodie TG. The bronchial muscles, their innervation and the action of drugs upon them. J Physiol 1903;29:97–173. 3. Bullen SS. Incidence of asthma in 400 cases of chronic sinusitis. J Allergy 1932;4:402– 8. 4. Gottlieb MS. Relation of intranasal sinus disease in the production of bronchial asthma. JAMA 1925;85:105–9. 5. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984;73:526 –9. 6. Friedman R, Ackerman M, Wald E, et al. Asthma and bacterial sinusitis in children. J Allergy Clin Immunol 1984;74:185–9. 7. Slavin RG. Relationship of nasal disease and sinusitis to bronchial asthma. Ann Allergy 1982;49:76 – 80. 8. Werth G. The role of sinusitis in severe asthma. Immunol Allergy Prac 1984; 7:45–9. 9. Brugman SM, Larsen GL, Henson PM, et al. Increased lower airways responsiveness associated with sinusitis in a rabbit model. Am Rev Respir Dis 1993;147:314 –20. 10. Bucca C, Rolla G, Scappaticci E, et al. Extrathoracic and intrathoracic airway
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15. 16. 17. 18. 19. 20. 21. 22.
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responsiveness in sinusitis. J Allergy Clin Immunol 1995;95:52–9. Global strategy for asthma management and prevention. NHLBI/WHO Workshop Report, NIH, NHLBI, January 1995, publication no 95-3659: 47– 60. Mallozi MC, Sole´ D, Naspitz CK. Broncoprovocac¸a˜o com histamina e metacolina em crianc¸as com e sem asma broˆnquica. J Pneumol 1991;17: 69 –73. Chai H, Farr RS, Roehlich LA, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975;56:323–7. Polgar G, Promadhath V. Pulmonary function testing in children: techniques and standards. Philadelphia: WB Saunders, 1971:1–152. Mygind N. Conventional medical treatment: “nasal allergy.” Oxford: Scientific Publications, 1978;257–70. Siegel S. Estadistica no parametrica. 2ed. Me´xico: Editorial Trillas, 1975: 1–346. Hollander M, Wolfe DA. Nonparametric statistical methods. New York: John Wiley Sons, 1973;1–503. Sokal RR, Rohlf FJ. Biometry. San Francisco: Freeman, 1969;1–776. Minor MW, Lockey RF. Sinusitis and asthma. South Med J 1987;80:1141–7. Younis RT, Lazar RH. The approach to acute and chronic sinusitis in children. Ear Nose Thr J 1991;70:35–9. Kogutt MS, Swischuk LE. Diagnosis of sinusitis in infants and children. Pediatrics 1973;52:121– 4. Rachelefsky GS, Goldberg M, Katz RM, et al. Sinus disease in children with respiratory allergy. J Allergy Clin Immunol 1978;61:310 – 4. Evans EO, Sydnor JB, Moore WEC, et
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al. Sinusitis of the maxillary antrum. N Engl J Med 1975;293:735–9. Wald ER, Milmoe GJ, Bower A, et al. Acute maxillary sinusitis in children. N Engl J Med 1981;304:749 –54. Arruda LK, Mimica IM, Sole´ D, et al. Abnormal maxillary sinus radiographs in children: do they represent bacterial infection? Pediatrics 1990;85:553– 8. Hill MK, Sanders CV. Principles of antimicrobial therapy for head and neck infections. Infect Dis Clin N Am 1988;2(1):57– 83. Friday Jr GA, Fireman P, Sukanich A, Steinberg ML. Sinusitis. In: Naspitz CK, Tinkelman DG, eds. Childhood Rhinitis and Sinusitis. New York: Marcel Dekker, 1990:193–215. Meltzer EO, Busse WW, Druce HM. Assessment of flunisolide nasal spray vs. placebo as an adjunct to antibiotic treatment of sinusitis [Abstract]. J Allergy Clin Immunol 1992;89:301. Melen I, Friberg B, Andreasson L, et al. Effects of phenylpropanolamine on ostial and nasal patency in patients treated for chronic maxillary sinusitis. Acta Otolaryngol 1986;101:494 –500. Spector SI, Farr RS. A comparison of methacholine and histamine inhalations in asthmatics. J Allergy Clin Immunol 1975;56:308 –16. Townley RG, Bewtra AK, Nair NM, et al. Methacholine inhalation challenge studies. J Allergy Clin Immunol 1979; 64:569 –74.
Request for reprints should be addressed to: Gary S Rachelefsky, MD Allergy Research Foundation 11620 Wilshire Blvd Suite 200 Los Angeles, CA 90025
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: There appears to be an association between sinusitis and asthma. The effect on bronchial hyperresponsiveness of clinical therapy for sinusitis in children may help to decipher whether sinusitis and asthma are independent manifestations of the same disease. Objective: To evaluate the effect of clinical treatment for sinusitis in patients with rhinitis and/or asthma on symptoms and on bronchial hyperresponsiveness to methacholine. Methods: Open label, randomized, non-treatment control in a teaching hospital in Sa˜o Paulo, Brazil. Forty-six atopic and 20 normal children were studied. The atopic children consisted of 18 with allergic rhinitis (12 without sinusitis and 6 with sinusitis), and 28 children with rhinitis with asthma (13 with normal sinus radiographs and 15 with complete opacification of the maxillary sinuses). Methacholine PC20 was determined before and 30 days after treatment with nasal saline, sulfamethoxazole-trimethoprim, antihistamine/decongestant, and five days of prednisone. Sinus radiographs were also repeated. Results: The only patients with increase in methacholine PC20 were patients with rhinitis and asthma with opacified maxillary sinuses at entry and who at 30 days had normal sinus radiographs (P ⬍ .05). Conclusion: In this study, children with allergic rhinitis and sinusitis with asthma improved their bronchial hyperresponsiveness to methacholine and decreased their symptoms with appropriate response of their sinuses to clinical therapy. Ann Allergy Asthma Immunol 1997;79:70– 4.
INTRODUCTION For many years the association between sinusitis and asthma has been described. The first studies relating upper airways (nose, nasopharynx, and paranasal sinuses) and bronchi began with Kratchmer in 1870.1 He showed that chemical irritation of the nasal mucosa in cats and rabbits resulted in bronchoconstriction. Electrical and mechanical stimulation of the nasal
* Division of Allergy, Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of Sa˜o Paulo Escola Paulista de Medicina, Brazil. † Allergy Research Foundation, Los Angeles, California, USA. Received for publication August 22, 1996. Accepted for publication in revised form January 29, 1997.
70
mucosa resulted also in reflex bronchoconstriction.2 In the beginning of this century, several studies described the incidence of sinusitis in asthmatic patients varying between 12%3 and 90%.4 Later it was believed that sinusitis reflected only broader changes of the respiratory tract other than the indirect effect of the worsening of lower airway function; thus, until the 1970s little was published about the association of sinusitis with asthma. In 1984, Rachelefsky et al5 observed that children with asthma showed remarkable improvement of lower airway symptoms and pulmonary function after diagnosis and concomitant treatment of sinusitis. Other studies showed the same results whether the sinus disease was treated clinically6 or
surgically.7,8 There are no doubts that sinusitis and asthma do coexist. The key point is to know whether sinusitis and asthma are independent manifestations of the same disease or whether sinusitis by itself can trigger or aggravate asthma. More recently, evidence of increased lower airway responsiveness associated with sinusitis has been found.9,10 In this study, we evaluated nonspecific bronchial hyperresponsiveness (BHR) by methacholine challenge in children with perennial allergic rhinitis alone or associated with asthma and/or sinusitis. After clinical treatment of those children with sinusitis, the BHR was again determined to evaluate whether or not such intervention would alter BHR. PATIENTS AND METHODS Forty-six atopic children and twenty normal children were included in this study. (Table 1) The atopic patients were selected from 152 children with rhinitis and/or asthma, and in all of them radiographs of the paranasal sinuses were obtained. The radiographs were obtained with the patient in orthostatic position, in three views: frontonasal (Caldwell), nasomental (Waters), and lateral. Inclusion criteria for the study were normal radiographs without nasal and/or postnasal purulent secretions, and those with complete opacification of one or both maxillary sinuses (lateral), with or without nasal and/or postnasal purulent secretions. Patients were included in the study if they had either a normal radiograph or complete opacification of one or both maxillary sinuses.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
The group of atopic patients consisted of 18 children with perennial allergic rhinitis, 12/18 with normal radiographs and 6/18 with complete opacification of the maxillary sinus; and of 28 children with rhinitis associated with asthma, 13/28 with normal radiographs and 15/28 with complete opacification of the maxillary sinuses. All patients had standardized histories obtained5 to elicit symptoms of rhinitis and sinusitis. All patients with rhinitis had had continuous symptoms for at least 6 months (nasal obstruction, nasal pruritus, sneezing, and coryza). After physical examination, they showed at least four of the following signs: dark circles under the eyes, Dennie’s lines, nasal transverse groove, oral respiration, V shaped palate, dental malocclusion, hypertrophy of the lower nasal conchae, and colorless or “bluish” nasal mucosa. In the group of children with rhinitis associated with asthma (n ⫽ 28), the asthma was classified according to severity as mild, moderate, and severe.11 All 46 patients demonstrated positive skin prick tests (⬎3 mm wheal diameter to Dermatophagoides pteronyssinus extract—30,000 allergy units per mL, Dome/Hollister–Stier, Division of Miles Inc); this group was the atopic group. Appropriate positive control skin tests with histamine and negative control tests with saline were also applied. The methacholine PC20 was determined in the 46 patients using a provocative concentration of methacholine causing a 20% fall in FEV1.12,13 Forced expiratory volume in one second (FEV1) was obtained and expressed as a percentage of the predicted.14 Subjects were clinically reevaluated after 15 and 30 days of treatment. Repeat radiographs and methacholine challenges were obtained after 30 days of treatment. Normal children had no previous clinical history of chronic rhinitis or asthma, and had no family and personal history of atopic diseases. Skin prick tests with Dermatophagoides pteronyssinus were negative. For ethi-
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cal reasons, radiographs of the paranasal sinuses were not taken. Bronchoprovocation was performed only at entry. All subjects and parents provided statements of informed consent, and the study was approved by the Ethical Committee of UNIFESP-EPM. Clinical treatment Children with normal radiographs were treated only with intranasal saline for 30 days.15 Children with opacification of the maxillary sinuses were treated with our standard approach, which includes (a) intranasal saline; (b) prednisone (1 to 2 mg/kg/once a day/5 days); (c) sulfamethoxazole and trimethoprim (40 mg/kg/day of sulfamethoxazole and 8 mg/kg/day of trimethoprim, q 12h for 21 days); and (d) an antihistamine (azatadine) 1 to 2 mg and a systemic decongestant (pseudoephedrine) 30 to 60 mg, thrice/day for 21 days. All medications were administered concurrently. Thirty days after treatment, all study children were submitted to a new radiograph in orthostatic position: frontonasal (Caldwell) and nasomental (Waters). Again, they were classified according to absence or presence of opacification of the maxillary sinuses. The following groups were obtained: group 1 was normal children (n ⫽ 20); group 2, children with perennial allergic rhinitis with normal radiographs before and after treatment with intranasal saline (n ⫽ 12); group 3, children with perennial allergic rhinitis with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 6); group 4, children with perennial allergic rhinitis and asthma with normal radiographs before and af-
ter treatment with intranasal saline (n ⫽ 13); group 5, children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 8); and group 6, children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses before and after clinical treatment (n ⫽ 7). The following tests were used for analysis of the results: Wilcoxon,16 to compare FEV1 and PC20 FEV1 methacholine before and after 30 days of treatment for each group, each patient acting as his own control; KruskalWallis’ variance analysis by ranks16 supplemented by the multiple comparison test17 to evaluate differences for all the groups before treatment with regard to FEV1, PC20, FEV1 methacholine, and age; and one criterion variance analysis,18 supplemented by the Scheffe´ contrast test,18 to evaluate differences with regard weight and height for all the groups. Differences were considered significant if a P value of less than .05 was obtained. RESULTS Group 1 comprised normal children: 7 girls and 13 boys with ages ranging from 7 years to 13 years and 2 months. Group 2 comprised 4 girls and 8 boys (ages ranging) from 7 years and 8 months to 14 years and 10 months). Duration of rhinitis varied from 1 to 12 years. Only one patient reported nocturnal cough that disappeared after treatment (Table 2). Group 3 comprised six children, 2 girls (ages ranging from 9 years and 6 months to 14 years and 3 months), all with rhinitis. Upon entry into study
Table 1. Normal Children (group 1) and Atopic Children (groups 2,3,4,5, and 6) in Relation to Average Age (years/months), Weight (kg), and Height (cm)
Age Weight Height*
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 12)
Group 3 (n ⴝ 6)
Group 4 (n ⴝ 13)
Group 5 (n ⴝ 8)
Group 6 (n ⴝ 7)
10/2 35.1 138.0
11/7 36.7 145.5
11/0 41.0 145.6
10/2 33.8 135.5
9/9 32.5 135.4
9/9 29.4 131.6
Kruskal Wallis—significant difference: group 6 ⬍ groups 2 and 3, * P ⬍ .05, and groups 1,2,3,4,5, and 6 —see text.
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50% of the children complained of headache and 75% of nocturnal cough. Purulent rhinorrhea was observed in 50% and 75% had purulent postnasal drip. All symptoms and signs disappeared after treatment, and radiographs of the maxillary sinuses became normal (Table 2). Group 4 comprised children with perennial allergic rhinitis associated with asthma, 4 girls and 9 boys (ages from 7 years and 5 months to 13 years and 10 months). Duration of rhinitis varied from 1 to 12 years, and asthma from 1 to 9 years: 3 were mild and 10 were moderate. Upon admission, nocturnal cough was the only symptom reported by 23.1% patients. After treatment, nocturnal cough persisted for only one of them. Purulent secretions were not observed upon admission (Table 2). Group 5 comprised eight children with perennial allergic rhinitis associated with asthma, 7 males (ages from 8 years to 13 years and 8 months). Duration of rhinitis varied from 2 to 12 years and of asthma from 4 to 12 years. According to the severity of asthma, 6 had mild, 1 moderate, and 1 severe. Headache was reported by 25% and nocturnal cough by 75% of patients upon admission. Half of them presented purulent coryza and purulent postnasal drip. All symptoms and signs were normal after treatment (Table 2). Group 6 comprised seven children with perennial allergic rhinitis associated with asthma, 6 males (ages from 7 years and 4 months to 11 years and 7 months). Duration of rhinitis varied from 2 to 10 years and of asthma from
5 years to 11 years 3 months. Three patients were affected by mild asthma, 2 by moderate asthma, and 2 by severe asthma. All of them had nocturnal cough, and 57% complained of headache. Purulent coryza was observed in 42.8% and purulent postnasal drip in 71.4%. Nocturnal cough after treatment disappeared in two patients only. Headache, purulent coryza, and purulent postnasal drip was observed in three different patients (Table 2). All groups were similar for age and weight. In relation to height, children of group 6 were of medium height (131.6 cm), significantly shorter than those of the groups 2 (145.5 cm) and 3 (145.6 cm) (Table 1). At admission, significantly lower values of FEV1 were observed in group 6 (75.6%), when compared with group 1 (96%). There were no significant differences between the groups of atopic children (Table 3). There were no differences between FEV1 values before and after treatment. Values of PC20 FEV1 methacholine determined before and 30 days after beginning of treatment for all groups are shown in Table 3 and Figure 1. Average basal value for the controls was 21.08 mg/mL; for those with rhinitis (groups 2 and 3) values were lower (15.08 and 10.70 mg/mL, respectively), and the lowest values (0.88; 0.76 and 2.91 mg/mL, respectively) were observed for those with perennial allergic rhinitis associated with asthma (groups 4, 5, and 6). PC20 FEV1 of methacholine of 4 mg/mL is the cutoff value for asthma.12 The comparison of PC20 FEV1 methacholine
Table 2. Clinical Symptoms and Signs of the Atopic Children (groups 2,3,4,5, and 6) Evaluated on Day Zero (0) and After 30 Days of Treatment (30)
Days
*Nocturnal cough *Headache *Purulent coryza *Purulent postnasal drip
Group 2 (n ⴝ 12)
Group 3 (n ⴝ 6)
Group 4 (n ⴝ 13)
Group 5 (n ⴝ 8)
Group 6 (n ⴝ 7)
0
30
0
30
0
30
0
30
0
30
1 0 0 0
0 0 0 0
4 3 3 4
0 0 0 0
3 0 0 0
1 0 0 0
6 2 4 4
0 0 0 0
7 4 3 5
5 1 1 1
* Number of patients with symptoms/signs: Groups 2,3,4,5 and 6 —see text.
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values upon admission (day 0) showed that the group 1 values were significantly higher than those of groups 4, 5, and 6. The group 2 values were significantly higher than those of groups 4 and 5 (Table 3 and Fig 1). PC20 FEV1 methacholine mean values from patients belonging to the allergic groups obtained after treatment showed a slight decrease for patients of groups 2 (10.83 mg/mL) and 3 (8.14 mg/mL). For patients of groups 4, 5 and 6, the mean values observed were 0.67 mg/ mL, 2.57 mg/mL, and 2.97 mg/mL, respectively. After treatment in the atopic patients, only group 5 showed a significant increase in PC20 FEV1 of methacholine: 0.76 to 2.57 mg/mL (Table 3 and Fig 1). DISCUSSION The main objectives of the clinical treatment of sinusitis are quick sterilization of the secretions and the re-establishment of ventilation, and drainage of the paranasal sinuses content.19,20 Radiologic changes of the paranasal sinuses in children with allergic rhinitis and/or asthma are observed frequently.21,22 In children with complete opacification of the maxillary sinuses or an air-fluid level, the recovery of bacteria in high counts from sinus aspirates would suggest that appropriate antimicrobial treatment of the sinus infection is important.23–25 Considering that Streptococcus pneumoniae was the main bacterial agent isolated in children with sinusitis in Brazil,25 the low socioeconomic level of the population studied and the easy administration of the drug, we used the combination sulfamethoxazole and trimethoprim to treat these patients for 21 days.19,20,26,27 Our atopic patients performed nasal hygiene with saline solution according to Mygind.15 Children with complete opacification of the maxillary sinuses, were also treated with prednisone, sulfamethoxazole and trimethoprim combination, antihistamine and systemic decongestant. Though there are few scientific data to reinforce the addition of other pharmacologic agents to the
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Table 3. Normal Children (group 1) and Atopic Children (groups 2,3,4,5, and 6), According to FEV1 (average, % predicted) and PC20 FEV1 of Methacholine Values (average, mg/mL) on Day Zero (0) and After 30 Days of Treatment (30)
FEV1 0 30 PC20 FEV1 0 30
Group 1
Group 2
Group 3
96.0 –
95.2 92.7
94.7 95.7
21.08 –
15.08 10.83
10.70 8.14
Group 4 87.3 83.3
0.88* 0.67
Group 5 83.9 88.5
0.76* 2.57†
Group 6 75.6* 82.1
2.91* 2.97
Kruskal Wallis day 0 (groups 1 ⫻ 2 ⫻ 3 ⫻ 4 ⫻ 5 ⫻ 6) FEV1 day 0 — group 1 ⬎ group 6, * P ⬍ .05 PC20 FEV1 day 0 — group 1 ⬎ groups 4,5 and 6 group 2 ⬎ groups 4 and 5, * P ⬍ .05 Wilcoxon (day 0 ⫻ day 30) FEV1, no significant differences PC20 FEV1— group 5: Day 0 ⬍ Day 30, † P ⬍ .05 Groups 1,2,3,4,5 and 6, see text
Figure 1. Normal children (group 1) and atopic children (groups 2,3,4,5, and 6), according to methacholine PC20 FEV1 (mean, mg/mL) on day zero (0) and after 30 days of treatment (30). Kruskal Wallis day 0 (groups 1⫻2⫻3⫻4⫻5⫻6). Group 1 ⬎ groups 4, 5, and 6. Group 2 ⬎ groups 4 and 5 ⫹ P ⬍ .05 Wilcoxon day 0 ⫻ day 30 Group 5: day 0 ⬍ day 30 *P ⬍ .05 Groups: 1 ⫽ normal children (n ⫽ 20), 2 ⫽ children with perennial allergic rhinitis with normal radiographs before and after treatment with intranasal saline (n ⫽ 12), 3 ⫽ children with perennial allergic rhinitis with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 6), 4 ⫽ children with perennial allergic rhinitis and asthma with normal radiographs before and after treatment with intranasal saline (n ⫽ 13), 5 ⫽ children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses and normalization after clinical treatment (n ⫽ 8) and, 6 ⫽ children with perennial allergic rhinitis and asthma with opacification of the maxillary sinuses before and after clinical treatment (n ⫽ 7).
proper antimicrobial therapy, there are enough theoretical and practical reasons to do it.19 In several conditions with underlying inflammatory processes corticosteroids have demonstrated efficacy.19,28 The probable beneficial effects of alpha-adrenergic agents include edema reduction of the
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nasal mucosa and decrease in the nasal resistance.29 We used antihistaminedecongestant combinations in our patients because they all presented with underlying atopic disease; nasal steroids were not used because of cost. Clinical data reported by the patients are shown in Table 2. There were sev-
eral prerequisites for admission to the study. Normal children and those with normal radiology of the maxillary sinuses (groups 2 and 4) were preselected. They were not admitted if purulent secretions were observed. There were no significant differences among the six groups studied relating to age and weight; however, the average height of the patients in group 6 (131.6 cm) was significantly shorter than that of groups 2 (145.5 cm) and 3 (145.6 cm) (Table 1). The main characteristics of group 6 were symptoms and signs of bacterial infection of the upper airways, frequently followed by aggravation of asthma. In addition, this group included two children with severe asthma and two with moderate asthma. Methacholine responsiveness is observed in asthmatic patients30,31 and many patients with allergic rhinitis. We observed higher values for PC20 FEV1 methacholine for normals, intermediate for pure rhinitics and lower when there was association with asthma (Table 3 and Fig 1). These data are similar to those observed by others.30,31 All asthmatic patients had low values of methacholine PC20 FEV1, regardless of the radiographic findings. Because of this, no relation between infection and BHR could be established. After 30 days of treatment, only in patients of group 5 was there a significant increase in the methacholine PC20 FEV1 values. In asthmatic patients, infection/inflammation in the maxillary sinuses may contribute to heightened bronchial hyperresponsiveness and appropriate clinical treatment of the sinusitis is important. This might be true only for asthmatic patients, since there were no changes in the BHR of rhinitic patients with sinusitis but without asthma (group 3). We recommend that the presence of sinusitis be considered in children with asthma who (1) have severe asthma, (2) do not respond to appropriate therapy, (3) have no obvious causes for their asthma, and (4) have associated significant upper airway symptoms. The presence of complete opacifica-
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tion of one or more maxillary sinuses, justifies aggressive pharmacologic intervention for sinusitis, resulting in improvement in symptoms and BHR.
11.
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Request for reprints should be addressed to: Gary S Rachelefsky, MD Allergy Research Foundation 11620 Wilshire Blvd Suite 200 Los Angeles, CA 90025
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