Pulmonary
Function
Abnormalities
in Symptom-free
Children
After
Bronchiolitis
Meyer Kattan, M.D., C.M., Thomas G. Keens, M.D., Jean-Guy Lapierre, M.D., Henry Levison, M.D., A. Charles Bryan, M.B., B.S., and Bernard J. Reilly, M.B., B.S.
From tile Department of Pediatrics and The Research institute, Hospital for Sick Children, (Jnicersity of Toronto
ABSTRACT. Twenty-three children less than 18 months old
who had clinical and radiological evidence of bronchiolitis
and remained symptom-free thereafter were studied to determine pulmonary function ten years later. Abnormal
Pao2, V,0Vand RV/TLC ratio were found in the majority of
subjects, and 31.3% had abnormalities in all three tests; four and one-half percent had exercise-induced bronchospasm. These changes indicate a residual parenchymal or airways
lesion following bronchiolitis. Pediatrics, 59:68.3-688, 1977, BRONCHIOLITIS, LUNG, PULMONARY FUNCTION.
The principal lesion in bronchiolitis, an acute illness affecting infants, is an inflammatory obstruction of the small airways. The pathology reveals necrosis of bronchiolar epithelium fol-bowed by lymphocytic infiltration of the bron-chial wall and narrowing of the lumen.’
Several studies have demonstrated that there is a high incidence of further wheezing or asthma subsequent to acute bronchiolitis, even if the etiology is known to have been viral.23 Some investigators have suggested that the same abnormal mechanisms operate in bronchiobitis as
in asthma.4 However, a large number of children never have a recurrence of wheezing after one or
two
episodes of bronchiolitis.Bronchiolitis affects small airways during a period of rapid lung growth. Disease of the small airways is thought to be common to various chronic obstructive lung diseases in adulthood, and there is evidence that these airways are the site of the earliest changes.5 Therefore, we studied the effect of bronchiolitis on subsequent pulmo-nary function in asymptomatic children with no previous history of asthma after a ten-year inter-val.
(Received July 23; revision accepted for publication September 10, 1976.)
Presented in part at the Society for Pediatric Research, April 29, 1976, St. Louis.
Dr. Keens is a Clinical Fellow of the U.S. Cystic Fibrosis Foundation.
Dr. Lapierre is a Fellow of the Quebec Medical Research Council.
MATERIAL AND METHODS
The charts of children between 1 and 18 nionths of age who had been hospitalized at the Hospital for Sick Children for bronchiolitis during
J
anuary to March 1965 were reviewed. The criteria for the diagnosis of bronchiolitis included tachpnea, retractions, rhonchi amid prolonged expiration on aimscultation, and hperaeration on chest X-ray. Only children with less than three episodes of bronchiolitis before 18 months who reniained free of wheezing and respiratory illness after that were included in the study. Children with cardiac or other pu1monar abnormalities were excluded.Omie hundred six childremi met the criteria. Only 27 children could be contacted, 23 of whom agreed to participate, with parental consent- 11 boys amid 12 girls. A careful history was obtained to exclude stmbjects with asthmatic symptomiis
(
namiiely, recurrent attacks of wheezing) and noctu rnal and postexertional wheeze amid cough. The childremi were examnimied to make certain they were asmptoniatic at the time of the study. Nomieof them had an tipper respiratory tract infection
iii the six weeks prior to the study.
The total lung capacity (TLC) amid its subdivi-siomis amid airways resistance were measured usimig a variable pressure l)ody plethsmograph by the
techmiiques described
by
Dubois et al.7 Specific ai rway comidtmctamice (SGaw) was determ med froniairways resistamice and the simultamieotmsly
meas-tired thoracic gas volunie. The pulmonary diffus-ing capacity for carbon monoxide (D1,co) was miieasimred by the single breath method.8 Oxygen amid carbon dioxide tensions (Pao2 and Paco2)
were miieasured iii arterialized blood ten minutes after application of a vasodilator cream according to a rigidly standardized techmiiqtme.’
Forced vital capacity (FVC), forced expiratory
volunie imi one secomid (FEy,), amid maximal expi-ratory flow l)etween 25% and 75% of vital capacity
(MMEF2:7)
were recorded with a 9-liter, water-filled Collins spirometer. Peak flow rates (PEFR) were measured with a Wright peakflow meter.
Maxiiiium expirator flow volumiie (MEFV)
curves were ol)taimied by use of a wedge
spirom-eter (Med Sciemice miiodel 270) miieasuring both flow amid volunie at the niouth. Curves were an-alyzed, and flow rates were reported from 50% amid 25% of vital capacity
(Y,,,
\). The flow at 6()% of total limmig capacity (\TLC) wasstandard-ized for differimig lung volimmes Ivy dividing the flow rates by the observed TLC amid expressed as TLC/sec.’ In additiomi, in 16 children MEFV
curves were obtained after a ten-minute equili-bration breathing a mixture containing 80% helium and 20% oxygen. The volume of isoflow (V0V) was derived by visually superimposing the flow volume curves obtained while breathing air on those obtained while breathing the helium-oxygen mixture. The volume where the flow rates for the two gases became identical was expressed as a percent of the vital capacity (VC).
Exercise studies were carried out on a treadmill at 5 KPH with a slope of 15 degrees. The children ran for six minutes, achieving a heart rate of at least 170 beats per minute, and PEFR was deter-mined at four and six minutes during exercise. MEFV curves and PEFR were obtained at inter-vals of approximately 3, 6, and 1 1 minutes after exercise. A 15% drop in PEFR from the resting value was taken as a significant response to exercise.
Amiy result was considered abnormal if it was mi#{238}orethan two standard deviations from the regressiomi line of normal from standards obtained in this laboratory.”
RESULTS
The subjects studied were all 1 1 years old. When these children were admitted to the hospital in infancy, the mean age was 3.6 ± 2.0
mrionths, and the mean length of hospital stay was 6.3 ± 3.5 days. Two children had allergies to
pollen and had received hyposensitization thera-py for allergic rhinitis.
The results of the pulmonary ftmnction tests are given in Table I. FVC and FEV, were normal in all the subjects. One subject (No. 11) had an MMEF significantly below normal. All the subjects had normal \, \(). Three subjects had
significantly reduced V( TLC sec ‘. The group
miiean for this parameter was 0.619 TLC sec ‘ ± 0. 1 76, which differed significantly from
the nornial value of 0.86 ± 0.25 (P < .005). Figure 1 is a graph of RV/TLC, showing the individual data points of the subjects amid the regression line with 95% confidence limits derived from a group of normal children studied in this laboratory. Nine of 22 children (40.9%) had an RV/TLC ratio greater than two standard deviations above the mean.
Figure 2 shows the results of Pao2 measure-mnents. The regression line with 95% confidence limits is derived from a group of 60 carefully screened, normal children. Eighteen of 23 chil-dren (78.3%) had oxygen tensions less than two standard deviations below the mean.
Subjects FVC (% FEy, (% MMEF (% V ,, RV/TLC Pao2 D,co SGaw V,V Predicted) Predicted) Predicted) (TLC/sec) (%) (torr) (ml/nmin/
torr)
(sec ‘
Clii H20)
(%)
0.727 26.6 87
0.507 23.5 70t
1 (RB) 109 91 120 19.6 0.222 25.7t
2 (CB) -j-j-:-
jo-
-- 12 0. 185 l7Mt3 (KB) -:- -;- 0.221t 39.8t 70t 159 0.101 1f9t
4 (RB) 94 87 96 0.687 27.4 81t 22.7 0.279 ND
5 (AC) 102 79 98 0.550 27.1 90 20.6 0.341 9.3
6(MC) 94 88 105 0.711 30.2t 74t 18.7 0.228 ND
7 (PC) 76 89 87 0.574 31.3t 84t 25.5 0.148 ND
8 (JD) 86 92 98 0.739 30.9t 73t 18.5 0.226 7.4
9 (FD) 99 77 72 0.348t 31.lt 76t 18.6 0.1.16 16.lt
10 (JD) 94 78 65 0.796 20.4 87 20.2 0.173 16.lt
ii (PF) 84 78 58t 0.617 21.4 74t 19.5 0.124 i3.8t
12 (KH) 92 89 120 0.857 16.4 81t 17.8 0.178 ND
13 (SH) 96 87 91 0.653 24.8 83t 16.9 0.373 ND
14 (CL) 74 98 100 0.808 31.3t 70t 14.5 0.323 17.lt
15(PL) 102 79 78 0.434 23.0 97 17.2 0.288 11.5
16 (CM) 107 75 71 0.348t 31.4t 72t 21.4 0.151 28.3t
17 (DM) 92 82 88 0.610 30.2t 76t 19.1 0.134 18.Ot
18 (FP) 73t
19 (AP) 100 82 88 0.764 14.0 85t 17.9 0.130 23.Ot
20 (TS) 87 83 75 0.435 33.4t 77t 15.9 0.179 9.1
21 (CS) 90 92 102 0.863 21.3 86 14.5 0.191 ND
22 (JV) 110 86 94 0.649 28.4 68t 21.7 0.281 18.2t
23 (JW) 84 79 93 0.721 28.2 78t 15.2 0.224 17.3t
#{176}FVC= forced vital capacity; FEy, = forced expiratory volume in one second; MMEF maximal midexpiratorv flow rate;
Vs,, flow at 60% of the TLC; RV = residual volume; TLC total lung capacity; D,CO = diffusing capacity; SGaw =
spe-cific conductance; V,,V = volume of isoflow.
t
More than 2 S.D. from the mean. ND = not done.§Subject was mentally retarded and unable to perform the tests adequately. TABLE I
RESULTS OF PULMONARY FUNCTION TESTING’
shown in Figure 3, with the regression and 95% confidence limits taken from normal children in our laboratory. Twelve of 16 children (75%) had a volume of isoflow greater than two standard deviations above the mean.
In the 16 children who underwent all the tests, including V,0V, the abnormalities were consistent (Fig. 4). Twelve of 16 (75%) had abnormal (Pao2,
1 1 of 16 (62.5%) had abnormal Pao2 and V0V, and five of the 16 (31.3%) had abnormalities in all three tests, the Pao9, V1,0 and RV/TLC ratio, ten years after the episode of acute
bronchioli-tis.
The results of exercise testing are shown in Table II. All subjects had normal resting PEFR. One subject had a greater than 15% drop in PEFR following exercise provocation. The chest X-ray
films were normal in all the subjects. Only three subjects were completely normal.
DISCUSSION
In this study we have attempted to screen out by history those patients who develop asthma following bronchiolitis. On exercise testing, the miiajority of this group failed to show a response to exercise provocation, a finding that one would expect in children without asthma. Only 4.5% of the bronchiolitic group showed exercise-induced bronchospasm (EIB) versus a reported incidence of EIB in asthmatic children of over 60%.’’
.
.
.
#{149}1
:
. . 7
2
1
11
12
AGE
(years)
FI;. 1. Restmlts of RV/TLC ratio versus age in 22 subjects after l)ronchiohtis. Individual data points and the least
ituares regression line with 95% confidence limits are shown.
.
11
12
AGE
(years)
(%)
RV/TLC
asthma by history, and the lack of EIB, the miiajorit of this groump of children demonstrated evidemice of hyperinflation, abnormal gas ex-change, amid/or small airways disease.
The data then raise two questions: (1) what is going on in the lung, and (2) what are the consequmences of this process?
Hperimiflation, manifested by the elevated RV/TLC ratio and the reduced ,, TLC, is
evidence for small airways obstrumction.” The low oxygemi tension demonstrates some abmiormality of gas exchange. Bronchiolitis may result in somie
obstructive damage or loss of recoil to some of the peripheral airways, causing ventilation perhmsion abmiornialities.
-The high V,,Vis also consistent with airways obstruction, with or without loss of elastic recoil. Flow is density-dependent in normal persons at lung volumes greater than 20% of the VC.’4 At these volumiies, the equal pressure poimit (EPP) is
ill the larger airways and the resistance upstream is caused mostly by convective acceler-ation and turbulence, both of which are density depemident. Iii the last portion of the VC, Mnax is demisity imidepemident.’4 This is because, at these volunies, flow is laminar as the EPP moves to sniall airways. When gases of different densities are used, flow rates will be the same only at the point where flow is laminar, i.e., in the peripheral airways. When resistance increases or there is loss of elastic recoil, the EPP will move closer to the
Pa02
(mmHg)
FIG. 2. Results of Pao versus age in 23 subjects. Individual data points are plotted with nean and two standard
(levia-tions above and below the mean shown.
alveoli; laminar flow will occur at higher lung volumes than is normal, and V,0Vwill then be higher. The sensitivity of this test in detecting diseases of the small airways in children has been
previously 7
The SGaw and PEFR were normal, indicating that the large airways were not affected. The FEV, and MMEF, although dependent on func-tion in both large and small airways,’8 are not as semisitive as are the V,0V and VmTLC in
detec-ting small airways disease.
The physiologic abnormalities could be ex-plained on the basis of loss of elastic recoil or peripheral airways obstruction. Loss of recoil miiight result from interruption of alveolarization during a period of extremely rapid lung growth. However, it is more probable that the primary lesion is in the airways. During the acute phase of bronchiolitis, Wohl et al.” have shown that there is an abnormally high airways resistance. In fact, follow-up studies showed that some of the chil-dren had abnormalities in resistance 11 months after the acute episode. The normal airway conductance in our group of subjects is not inconsistent with the findings of Wohl et al. or the hypothesis of airways disease. The peripheral
airways contribute little to the total airway resistance after 5 years of age, and obstruction in these airways would not be expected to result in a high resistance or low conductance.2#{176}
.
.
. . .
#{149}#{149}#{149}
10’
11
12
AGE
(years)
Subjects
ABNORMAL
Viso
(%
VC)
2
Pa02 P002 #{176}O2
+ +
Viso’ Viso’’ + RV/TLC
FIG. 4. Percent of subjects with ibnormal Pao9, V ,,V+ Pao,
and Pao. + V,,V+ RV/TLC.
FIG. 3. Volume of isoflow expressed as percent of vital capacity versus age in 16 subjects. The mean is depicted with
two standard deviations above the mean.
TABLE II
bronchiolitis in a 6-year-old child and in an adult who had no clinical evidence of respiratory disease. This finding was explained by the large increase in conductance after 5 years of age, making airway disease difficult to detect clii-cabby. The same situation may exist in our subjects. The abnormalities detected may be a result of residual bronchiolar damage subsequent to infection in a growing lung.
Bronchiolitis in infancy apparently is not a benign disease. Besides the high incidence of asthma following acute bronchiolitis, the present data show that there is a residual parenchymal or airways lesion affecting the majority of the patients. Whether or not this lesion is reversible given more time and further lung development remains unknown at present.
However, after 10 years of age, and when lung growth is almost complete, it seems highly probable that this is a permanent defect. As bronchiolitis is a common disease resulting in a residual defect in most patients, this may account for the extremely wide range of normal values for most pulmonary function tests. One can also speculate that the presence of a residual paren-chymab or small airways lesion might increase the sensitivity of the lung to exogenous factors, such as smoking, and be one of the risk factors predis-posing to chronic obstructive lung disease.
EFFECT OF EXERCISE ON PEAK EXPIRATORY FLOW RATE
Resting PEFR
(#{176}/Predicted)
i (RB)
c
7.1 02 (CB) 94 8.6 0
(KB) 75 0 17.3#{176}
4 (RB) 88 4.9 4.9
_______________________________________
114 9.6 1.4
6 (MC) 107 4.6 13.8
‘2’ (PC) 100 10.5 0
8 (JD) 94 8.3 3.3
9 (FD) 92 6.7 10
10 (JD) #{149} 102 0 10.5
ii (PF) 90 11.1 1.3
12 (KH) 102 14.7 0
13 (SU)
o
5.9 5.914 (GL) 5.9 2.9
PL) 102 5.9 5.9
16 (CM) 97 14.2 0
17 (DM) 102 0 5.9
*‘ 94 6.7 6.7
20 (TS) 85 5.9 2.0
21 (CS) 90 10.1 1.8
#{149}22 (JV) 1 1 1 1 1 .5 1.3
23 (JW) 105 0 4.8
‘More than 2 S.D. from the mean.
% Rise % Fall
in PEFR in PEFR
SUMMARY
The pulmonary function of 23 asymptomatic children was studied 10 years after acute bron-chiolitis. We attempted to screen out by history those children who developed asthma subsequent to bronchiolitis. The majority of this group of children demonstrated evidence of hyperinfla-tion, abnormal gas exchange, and/or small airways disease. There were 31.3% of the subjects who had abnormalities in all three tests-the Pao9, the V1,0% and the RV/TLC ratio. These abnor-malities are thought to be on the basis of loss of elastic recoil or peripheral airways obstnmction.
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ACKNOWLEDGMENT
We would like to thank R. Blanche for technical assistance
