Increased incidence of bronchial reactivity in children with a history of bronchiolitis

April 1981 The J o u r n a l o f P E D I A T R I C S

551

Increased incidence of bronchial reactivity in children with a history of bronchiolitis To assess bronchial reactivity in children who have had bronchiolitis, we studied 48 children by challenging them with methacholine nine or ten years after admission to hospital with bronchiolitis. Pulmonary function was also evaluated. Fifty-seven percent o f children studied had bronchial hyperreactivity. Thirty-three percent of first-degree relatives of those with a positive M C H challenge had a positive response. There was a significant correlation between the occurrence o f a positive M C H challenge and a history o f recurrent bronchiolitis. Pulmonary function tests demonstrated lower flow rates in the positive responders. Fourteen children had a history o f asthma or wheezing, but this did not appear to be severe or frequent, and few required long-term therapy. There appears to be a strong genetic component in the prevalence of bronchial reactivity in these children. Bronchial hyperreactivity may be a risk factor in the development o f COPD.

Dennis

Gurwitz, M.B., B.Ch., C a t h y

Mindorff,

R.N.,

and H e n r y Levison, M.D.,* T o r o n t o , Ont., C a n a d a

BRONCHIOLITIS in infancy (under 2 years of age) is characterized by an acute onset of wheezing, cough, dyspnea, and rhinorrhea with evidence of obstructive pulmonary hyperinflation on physical and radiologic examination. 1 Most investigators have established that the etiology is infectious, with viral agents being the most common organisms. ~ Previous studies have confirmed that wheezing can follow bronchiolitis, irrespective of the etiology.3-" An almost universal feature of asthma is an increase in nonallergic bronchial responsiveness to vasoactive amines such as histamine and methacholineT; thus, bronchial challenges with these agents are frequently applied in the diagnosis and assessment of asthma? Although wheezing and asthma have been reported in a large number of children following bronchiolitis,:~-" the role of bronchial hyperreactivity has not been clarified in these children. ~, 9 In an attempt to resolve this issue, we assessed bronchial reactivity, as determined by methacholine challenge, in children who had a history of apparent virus-induced bronchiolitis in infancy and in a number of their first-

From Department o f Pediatrics and the Research Institute, Hospital f o r Sick Children. *Reprint address: The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8.

0022-3476/81/040551 +05500,50/0 9 1981 The C. V. Mosby Co.

degree relatives. In addition, we assessed the clinical manifestations of bronchial hyperreactivity in these children, and their pulmonary function. METHODS The charts of all the children who had been hospitalized at the Hospital for Sick Children for bronchiolitis in Abbreviations used methacholine MCH: chronic obstructive pulmonary disease CO PD: forced expiratory volume in one second FEV,: methacholine dose needed to produce PD~0: 20% fall in FEV, forced vital capacity FVC: MMEF25-75%: maximum mid-expiratory flow between 25 and 75% total lung capacity TLC: specific conductance SGaw: peak expiratory flow rate PEFR: residual volume/total lung capacity RV/TLC: 1969 and 1970 were reviewed. One hundred and forty-five children who were admitted during this period met the criteria for the diagnosis of bronchiolitis. 1Five had mental retardation. We attempted to contact the remainder for follow-up studies. Forty-eight agreed to participate with parental consent, nine to ten years after the index admis-

Vol. 98, No. 4, pp. 551-55

552

Gurwitz,Mindorff, and Levison

The Journal of Pediatrics April 1981

Table I. Results of methacholine challenge in children with bronchiolitis

Total No. of subjects Present age (yr) (mean) Age at index Admission (too) (mean) 1-2 attacks 3 + bronchiolitis Wheezing

I MCH I MCH pos* negt

RB~

1-2w

48

27

20

25

23

10.4

10.3

10.5

10.6

10.3

7.6 23 25 14

7.5 8 19 12

8.3 14 6 2

9.0 0 25 14

6.4 23 0 0

Age Range = 9-12years; one MCH not completed. *MCH pos = Methacholinepositive. ~'MCHneg = Methacholinenegative. :~RB = Recurrentbronchiolitis. w B = One to two attacks of bronchiolitis. sion to hospital. A careful history was obtained of the frequency of wheezing, any possible factors precipitating wheezing, the occurrence of asthma, eczema, or seasonal rhinitis, and any other respiratory illness. A routine physical examination was performed. All subjects were nonsmokers and none had had an upper respiratory tract infection within four weeks prior to the study. All bronchodilator medications were discontinued 12 hours prior to the study. Forty-eight subjects were challenged with methachofine. One subject was incapable of completing the test because of the taste of the methacholine. In all patients, we used the standard method described by Chai et al. TM From the cumulative amounts of methacholine inhaled and the corresponding drops in FEV~, a dose-response curve for methacholine was constructed. The dose of methaeholine required to produce a 20% fall in FEV1 is referred to as PD20 and was calculated from the dose response curve (cumulative breath units). In addition, 66 first-degree relatives, parents and siblings of 24 study subjects with a positive methacholine response, were challenged with methacholine. Forced vital capacity, forced expiratory volume in one second, and maximum mid-expiratory flow between 25 and 75% of vital capacity (MMEF25_75%) were recorded with a nine litre Collins water-filled spirometer. Total lung capacity and airway resistance were measured using a variable pressure body plethysmography by the techniques described by Dubois et al. TM 12 Specific conductance was calculated. Peak expiratory flow rate was measured with a Wright peak flow meter. Normal values of pulmonary function were obtained from normal children studied in our laboratory. 13 All statistical comparisons or means were done using two-

tailed t tests and the chi square was used, to compare different groups. TM RESULTS Subjects. Forty-eight subjects were studied, 30 boys and 18 girls. The clinical summary of the study group is shown in Table I. When these children were admitted to hospital in infancy, their ages ranged from 2 to 23 months. Although the number of hospital admissions for bronchiolitis varied from one to four (mean 1.5), some children had additional episodes of bronchiolitis not requiring hospital admission. Fourteen children had a history of wheezing and eight of these had been diagnosed by their own pediatrician as having asthma. All children had a normal physical examination with the exception of two children with asthma who had rhonchi on the day of the study. One child had had a previous repair of a patent ductus arteriosus. Pulmonary function. Baseline studies showed the majority of pulmonary function tests to be within 2 SD of normal limits established by normal children studied in this laboratory. 13 However, abnormal results were seen. The vital capacity was low in five children, FEV1 was low in nine (seven positive methacholine responders), MMEF25_75%was low in six (all methacholine positive), PEFR was low in four, TLC raised in three, and residual volume/total lung capacity ratio raised in 20 (17 methacholine positive). Bronchial reactivity. Twenty-seven of 47 children (57%) had a positive methacholine response. These patients were less sensitive to methacholine than asthmatic patients previously studied in this laboratory? ~ The PD20 of the postbronchiolitis group, 62.7 _+ 55.1, was significantly greater than that of the group of asthmatic patients studied, 18.9 + 21.2 (P < 0.001)? ~ The subjects were divided into two groups-those with a positive methacholine response and those with a negative methacholine response. Table I shows the clinical data and Table II the pulmonary function of the two groups. There was a significant difference between the two groups in RV/ TLC, VC, F E V , MMEF25_75%, and SGaw. There was a significant correlation between positive methacholine response and recurrent bronchiolitis (P < 0.02). There was no relationship to the age at the index admission to hospital. Of the 14 children with a history of wheezing or asthma, 12 had a positive response to methacholine. Fanfily studies. Sixty-six first-degree relatives of 24 children with a positive methacholine challenge were studied. There were 41 parents and 25 siblings. Eleven of 41 parents and 11 of 25 siblings (33% of total) had a positive methacholine challenge. Recurrent bronchiolitis. Based on the total number of

Volume 98 Number 4

Bronchial reactivity in children with bronchiolitis

SENSITIVITY OF METHACHOLINE

25-

553

CHALLENGE

MCH POSITIVE

MCH NEGATIVE

20 ~ASTHMA, Z

ua

15

~)

]0-

I'/////;,IWHEEZING

'//A

~

~

o

............

,oo Z

~Z

~o<

u~Z E,~

Z .~

~///~"

,so CUMULATIVE

BREATH U N I T S (PD2o)

w

~z ~-

u ~-

z

o

0

u

Figure. Graph showing the amount of methacholine necessary to produce a fall of 20% in FEV, (cumulative breath units). Majority of subjects were very sensitive to methacholine, requiring less than 50 CBU to produce 20% fall in FEVa. Shaded area are those with a history of asthma or wheezing. The means of previously studied groups of children with asthma (15), cystic fibrosis (15), and a history of croup (18) are shown.

Table II. Results of pulmonary function tests in children with a positive M C H response and in those with a negative M C H response

Test

I

MCH pos mean • SD (N)

MCH neg mean • SD (N)

Age (yr) VC (% pred) FEV~ (% pred) MMEF (25-75%) (% pred) RV/TLC (%) SGaw (sec-lcmH~O) FEV~/VC (%) PEFR (% pred)

10.3 _+_0.6 (27) 86.2 _ 9.47 (27) 80.85 • 10.61 (27) 69.63 • 22.13 (27) 30.86 • 6.46 (25) 0.181 • 0.062 (25) 81.68 • 10.24 (27) 84.93 • 19.56 (27)

10.5 +_ 0.8 (20) 94 • 11.45 (20) 87.4 • 9.86 (20) 83.45 • 17.11 (20) 25.53 _+_6.73 (20) 0.24 _+ 0.082 (20) 83.53 • 8.37 (20) 91.3 _+ 14.2 (20)

MCH

= Methacholine;

t

Significance level (P) NS <0.025 <0.05 <0.05 <0.02 <0.01 NS NS

pos = positive; neg = negative; NS = no significance.

attacks of bronchiolitis in hospital and at home, subjects were divided into those with recurrent bronchiolitis (more than two attacks) versus one or two attacks. Only the R V / T L C ratio was significantly different between the two groups, children with recurrent bronchiolitis having a higher R V / T L C ratio. All the children with a history of wheezing had recurrent bronchiolitis (P < 0.001). Hospital records. F r o m the hospital records, data were collected from the children who could not be contacted. Their m e a n age at admission was 6.4 months, n u m b e r of admissions 2.2 _+ 4.69, and there were nine children with a diagnosis of asthma made by their own pediatrician based on a history of recurrent wheezing. (No significant difference from study group.)

DISCUSSION Bronchial hyperreactivity has been found in a variety of respiratory disorders. It is almost universal in patients with asthmaS' 1~ 98% having hyperreactive airways. It is found to a lesser extent in atopic disease, TM chronic bronchitis and emphysema, 17 cystic fibrosis, Ix and in children who previously have had croup TM (Figure). There appears to be a spectrum of sensitivity among responders in respiratory disorders to nonspecific challenge tests, with asthmatic patients at one extreme and a very small proportion of healthy subjects at the other. We have found that children who have previously had bronchiolitis have a high incidence of bronchial hyperreactivity as defined by methacholine challenge. Other investigations

554

Gurwitz, Mindorff, and Levison

into bronchial reactivity after this illness have yielded conflicting results. Using exercise challenge, Sims et al ~ reported bronchial reactivity to be increased compared to that of normal controls. Katten et al, 9 on the other hand, did not observe a significant increase in exercise-induced bronchospasm following bronchiolitis. However, in the latter study the children had had only one or two attacks of bronchiolitis, and this difference may have accounted for the low incidence o f bronchial hyperreactivity. We used a more sensitive and quantitative challenge than exercise in determining bronchia! reactivity.TM The number of first-degree relatives (33%) with a positive methacholine response would suggest that there may be a genetic predisposition to the development of bronchiolitis and airway reactivity. This finding was compared to the results of methacholine challenges performed on first-degree relatives of children who had a positive methacholine response following croup; only one of 28 of these parents and siblings, who were of similar age and had a smoking history as in our families, had a positive methacholine response. 18Konig and Godfrey, s~in studying healthy relatives of children with "wheezy bronchitis," found 29% to have exercise-induced bronchial lability, which was very similar to that in relatives of children with asthma. One may postulate that there may be a common genetic basis for bronchial reactivity, producing a tendency toward wheezing. There is a growing consensus that bronchial hyperreactivity is an essential component of the asthmatic syndromeg; however, as shown above, it is not unique to asthma. A high degree of bronchial hyperreactivity does not establish a diagnosis of asthma. The Figure illustrates the spectrum of bronchial hyperreactivity found in the study group and, within the study group, in those with asthma and wheezing. The majority of those with a positive challenge have a high degree of airway sensitivity that overlaps that found in asthma or wheezing. Although as a group children who have had bronchiolitis have sensitive airways, they are not as sensitive as in those with asthma# but are more sensitive than in those with a history of croup. TM Two important questions emerge from these data; what are the current clinical manifestations of this degree of bronchial reactivity, and what are the long-term implications? Our incidence of recurrent wheezing was 29%. This finding is in keeping with previous reports.', 5. 21, z2 However, the overall clinical status is far more important than the isolated historical or clinical documentation of wheezing. Despite the high incidence of bronchial reactivity, we found that only a very small proportion of patients required constant or intermittent medication. Rooney and Williams3 had 21 children with more than ten episodes of

The Journal of Pediatrics April 1981 wheezing, but they did not mention how many actually required therapy for the wheezing. Sims et al e showed that although half o f their study group had subsequent episodes of wheezing, in most cases they were neither severe nor frequent. Does hyperreactivity of the airways represent an important risk factor in the development o f chronic obstructive pulmonary disease? Barter and Campbell 23 have shown minimal cigarette consumption in subjects with pronounced reactivity to be associated with serious losses in ventilatory function. Moreover, Britt et al, z4 in prospective studies over a four-year period in a small group of young, healthy sons of patients with COPD, reported that those with hyperreactive airways were losing lung function five times as fast as those without hyperreactive airways. We believe that children with hyperactive airways and a previous history of bronchiolitis may be at an increased risk for the development of COPD. The authors thank Emma Abad, Ruth Blanch, and Noli Tigas for their assistance in doing the pulmonary function testing, and Shelley Gelber who helped with the preparation of the manuscript. REFERENCES

1. Zweiman B, Schoenwetter WF, and Hildreth EA: The relationship between bronchiolitis and allergic asthma, J Allergy 37:48, 1966. 2. Chanock RM, Kim HW, Brandt CD, and Patron RH: Respiratory syncytial viruses, in Evans AS, editor: Viral infections of humans, New York, 1976, Plenum Publishing Corp, p 365. 3. Rooney JC, and Williams HE: The relationship between proved viral bronchiolitis and subsequent wheezing, J I~DIATR 79:744, 1971. 4. Wittig HJ, and Glaser J: The relationship between bronchiolitis and childhood asthma, J Allergy 30:19, 1959. 5. Eisen AH, and Bacal HL: The relationship of acute bronchiolitis to bronchial asthma-a 4 to 14-year follow-up, Pediatrics 31:859, 1963. 6. Sims DG, Downham MAPS, Gardner PS, et al: Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy, Br Med J 1:11, 1978. 7. Boushey HA, Holtzman MJ, Sheller JR, and Nadel JA: Bronchial hyperreactivity, Am Rev Respir Dis 121:389, 1980. 8. Menkes HA: Airway reactivity and the need for a simple test, Am Rev Respir Dis 121:619, 1980 (editorial). 9. Kattan M, Keens TG, Lapierre J, et al: Pulmonary function abnormalities in symptom-free children after bronchiolitis, Pediatrics 59:683, 1977. 10. Chai H, Farr RS, Froehlich LA, et al: Standardization of bronchial inhalation challenge procedures, J Allergy Clin Immunol 56:323, 1975. 11. Dubois AB, Bothelho SY, Bedell GN, et al: A rapid plethysmographic method for measuring thoracic gas volume, J Clin Invest 35:322, 1956. 12. Dubois AB, Bothelho SY, and Comroe JH: A new method

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19. Mellis CM, Kattan M, Keens TG, and Levison H: Comparitive study of histamine and exercise challenges in asthmatic children, Am Rev Respir Dis 117"911, 1978. 20. K0nig P, and Godfrey S: Exercise-induced bronchial lability and atopic status of families with wheezy bronchitis, Arch Dis Child 48:942, 1973. 21. Kubo S, Funabashi S, Uehara S, Toba T, Muramatsu Y, and Sanada K: Clinical aspects of "asthmatic bronchitis" and chronic bronchitis in infants and children, J Asthma Res 15:99, 1978. 22. Hyde JS, and Saed AM: Acute bronchiolitis and the asthmatic child, J Asthma Res 4:137, 1966. 23. Barter CE, and Campbel! AH: Relationship of constitution factors and cigarette smoking to decrease in l-second forced expiratory volume, Am Rev Respir Dis 113:305, 1976. 24. Britt JE, Cohen B, Menkes H, et al: Airways reactivity and functional deterioration in relatives of COPD patients, Chest 77(2 Suppl):260, 1980