THE SITE OF AIRWAY OBSTRUCTION IN CYSTIC FIBROSIS

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THE

SITE

OF

AIRWAY

OBSTRUCTION

IN CYSTIC FIBROSIS

E

VIDENCE has been presented that some patients with cystic fibrosis have sig-nificant amounts of obstruction to the

venti-lation of portions of lung, as indicated by

tests of the distribution of ventilation, but they have little or no evidence of obstruc-tion by conventional measurements of air-way resistance.15 This discrepancy may be

attributed to the fact that various tests of

pulmonary function differ in sensitivity

with respect to small and large airway

ob-struction. It is the purpose of the present

Commentary to summarize the evidence for

this hypothesis and to suggest that differ-ences in the extent to which measurements

of airway resistance and distribution of

ventilation are altered in patients with cys-tic

fibrosis

may be used to localize the site of obstruction and to follow the different stages in the natural history of the pulmo-nary disease.

DeMuth, Howatt, and Talner2 have

shown that a number of patients with cystic fibrosis have maximum

breathing

capacities

(MBC) in the normal range but abnormal

oxygen equilibration indices (OEI). The MBC, or the maximum volume of

ventila-tion which can be achieved voluntarily, is a

test of overall ventilatory capacity and falls as airway resistance rises. The OEI is a

measure of the rate of equilibration of lung

gases with gases in a closed system into

which

the

patient breathes; the value for OEI rises the more uneven the ventilation.

The

observation

that

a number of patients

fall

in the normal range for MBC but in the

abnormal range for OEI suggests that it is

possible to have a degree of airway

ob-struction which impairs ventilation to some

lung units without significantly altering a

conventional measurement of overall

air-way resistance.

The same conclusion is reached from an

analysis of the data reportedl34 on several patients with normal MBC or FEV#{176} and abnormal alveolar nitrogen after breathing

100% oxygen for 7 minutes or abnormal

expired nitrogen curves following a single

inhalation of 100% oxygen. The latter two

tests reflect uneven ventilation, suggesting

that some portions of lung are poorly

yen-tilated, presumably as the result of airway

obstruction. Although both the MBC and

FEy, have been used as indices of airway

obstruction, the two do not regularly

fol-low each other. Discrepancies have also

been noted between airway resistance

dur-ing quiet breathing and the FEy1.6

There are several possible explanations

for the differences in the extent to which

the MBC, the FEy,, and the airway

re-sistance are altered in individual patients. 1. It is very likely that direct

measure-ment of airway resistance during quiet

breathing quantifies different mechanical events from the FEV, or MBC since the

volume history of the lung, the flow

pat-terns, and the transpulmonary pressure are

different in the three procedures.

2. The MBC is influenced by such

fac-tors as patient effort and muscle strength.7

3. Analysis of the maximum expiratory

flow-volume curve of a patient with cystic

fibrosis (right panel of Fig. 1) suggests

another explanation for the apparent

dis-crepancies between the MBC and the

FEy1. This curve represents the maximum

achievable

flow at each lung volume

throughout

the vital

capacity.’

When

com-pared

with the normal curve (left panel

Fig.

1), maximum flow rates in cystic

fi-brosis are reduced to a greater extent at

low lung volumes than at high lung

vol-umes.5 By performing the MBC at a high

lung volume, this patient is able to achieve

high flow rates and hence a normal value

for the MBC. On the other hand, the FEy,

encompasses a portion of the vital capacity

#{149}FEY = measured time volume during a maxi-mally forced expiratory vital capacity breath. The

1-second volume (FEY1) expressed as a percent of the vital capacity is most widely used.

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NORMAL CYSTIC FIBROSIS

FEy1 ‘( 14-FEV1--#{248}I

C

FLOW

Lit /sec

4

0

3

2

e

FLOW

Lit/sec

0

2

316 CYSTIC FIBROSIS

3

3 2 I 03 2 0

LUNG VOLUME LUNG VOLUME

LIT LIT

Fic.1. Flow-volume curves of W.M., a healthy 12-year-old boy (left),and J.D., a 15-year-old girl with cystic fibrosis(right). Beginning at the end of a quietbreath, a, these were recorded during a normal

tidal breath (small loop) and during a forced expirationfrom peak inflation, b, to full expiration, e. Peak expiratory flow rate is reached at c. Expiration then continues along c-d-e. Each point on the expiratory portion of the flow-volume curve represents the maximum flow achievable at that lung volume. The time interval between each dot is 0.04 second. The volume of air expired in one second (FEY1)

is shown above the curves.

where flow rates are reduced below normal

and is therefore reduced.

The reason for the apparent discrepancy in the information provided by tests of air-way resistance and tests of gas distribution

is disclosed by some recent studies of

Macklem

and

Mead.8

By

an ingenious

method they were able to measure the

pres-sure directly in airways located in the tenth

to fifteenth generation and measuring 1.5 to

2.5 mm in diameter. They were thus

able to partition the airway resistance into

central or large airway and peripheral or

small airway resistance. Over most of the

range of the vital capacity, the peripheral resistance was 10% or less of the total resis-tance. Thus, a large increase in peripheral

resistance would result in only a small

increase in the total airway resistance. How-ever, this same increase in peripheral resis-tance could appreciably affect gas distribu-tion and exchange.

This study provides the theoretical

framework for picturing

the

location of the

airway obstruction in those patients with

relatively normal tests of airway resistance but abnormal tests of gas distribution. Air-way obstruction must reside in an area

which contributes little to overall airway

resistance, and hence it must reside in

the

small peripheral airways.

This

conclusion fits very nicely with the

pathological evidence that early in cystic

fibrosis it is the more peripheral airways or

bronchioles which are more severely

(3)

COMMENTARIES not, however, appear to fit with the conclu-sion that airway obstruction involves large airways in cystic fibrosis.5 Most of the pa-tients in the latter study were well along in

the natural history of their disease. They

had moderate to severe pulmonary

involve-ment on clinical and radiographic grounds

and would be expected to have

bronchiec-tatic changes in the larger airways.3’9” In

addition to physiological evidence for large airway obstruction, these studies provided

cineradiographic demonstration of large

airway collapse during forced expiration.

It now seems likely that there are two

sites of obstruction in cystic fibrosis. In the

early stage of pulmonary disease, the

ob-struction appears to be localized in small

airways, is present during inspiration and expiration, and is little affected by lung vol-ume. Differences in the magnitude of

obstruction from one region to another

ac-count for the abnormalities in tests of distri-bution of ventilation. As long as the large airways are unobstructed, measurements of

airway resistance may be close to normal.

Later in the course of the disease there is also large airway obstruction, which is due

to dynamic compression of airways; the

ob-struction is present only during expiration

and is markedly affected by lung volume.5

At this stage it may still be possible to find

relatively normal measurements of airway

resistance during quiet breathing. However,

the FEy, is likely to be reduced because of

the marked reduction in maximal flow rates as lung volume decreases (Fig. 1). Finally,

when mucus plugging and inflammation

in-volve the large airways, measurements of

airway resistance during quiet breathing

become elevated.

Separate sites of obstruction in small and

large airways have been demonstrated in

adults with “bronchitis and emphysema.”12 Whether there is a predictable sequence of

small and large airway obstruction in this

heterogeneous group of diseases is

un-known and will be difficult to ascertain

until there is greater precision in definition of the clinical type of obstructive disease.’3

Although the present analysis supports the

notion that small airway obstruction

pre-cedes large airway obstruction in cystic

fi-brosis, it remains to be determined how early in the natural history of the disease there is large airway obstruction either as the result

of dynamic compression of large airways or

mucus plugging and inflammation. This

in-formation may be of importance in decid-ing how early to administer mist, since the

bulk of particles formed by many

commer-cially available mist or fog generators settle in the large airways.’4

The difference in the extent to which

the various tests of gas distribution and

airway resistance are altered may now be

used to analyze the sites of obstruction in

cystic fibrosis and to follow the natural

history of the disease. Early in the disease

the finding of abnormal distribution of

ventilation despite relatively normal airway

resistance (either direct measurement of

airway resistance or indirect assessment by

the MBC or FEV), suggests that the airway

obstruction is localized primarily to the

smaller airways. Later in the course of the

disease, the finding of a reduced FEy, in

the presence of normal airway resistance

during quiet breathing suggests dynamic

compression of large airways. Whether the

FEY, detects dynamic compression at this

stage depends upon the extent to which

expiratory air flow is reduced in the lower

portion of the vital capacity (Fig. 1). For

this reason the maximum expiratory flow-volume curve may be a more sensitive indicator of dynamic compression than the

FEY,. Finally, the development of

in-creased airway resistance during quiet breathing suggests that there is intralumi-nal obstruction of large airways.

Detection of large airway obstruction by conventional roentgenograms,’5 as well as by cineradiography, is now possible. Until such time as the techniques used by Mack-lem and co-workers8”6 in living dogs and in

lungs at necropsy can be safely applied to

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inferen-318 CYSTIC FIBROSIS

tial. Nevertheless, under these

circum-stances, inferences drawn from combined

tests of distribution of ventilation and

air-way resistance seem justifiable and can be

of considerable help.

There are a number of different methods

for evaluating the distribution of

ventilation.’7 The tests are not difficult

technically and are usually performed in

conjunction with the measurement of the

functional residual capacity. Although

di-rect measurement of airway resistance is

difficult, indirect assessment by means of

the MBC or FEV is relatively easy. It is

also urged that airway dynamics be

as-sessed by means of the flow-volume curve.

A simple flow-volume device has been

de-scribed,’8 and normal values for children

have been reported.19

ROBERT B. MELLINS, M.D.

Department of Pediatrics of the College

of Physicians and Surgeons Columbia University

New York, New York 10032

Recipient of Career Development Award, No. 1-K3-HE-31, 667 National Institutes of Health, Public Health Service. Supported in part by Re-search Grant HE-08015 from the National Insti-tutes of Health, U.S. Public Health Service, with additional support from the New York Heart Asso-ciation.

REFERENCES

1. West,

J.

R., Levin, S. M., and Di Sant’Agnese,

P. A.: Pulmonary function in cystic fibrosis of the pancreas. PEDIATRICS, 13:155, 1954. 2. DeMuth, C. R., Howatt, W. F., and Tamer, N.

S.: Intrapulmonary gas distribution in cystic fibrosis. Amer.

J.

Dis. Child., 103:551, 1962. 3. Coldring, R. M., Fishman, A. P., Turino, G.

M., Cohen, H.

J.,

Denning, C. R., and An-dersen, D. H. Pulmonary hypertension and cor pulmonale in cystic fibrosis of the pan-creas.

J.

Pediat. 65:501, 1964.

4. Beier, F. R., Renzetti, A. D., Jr., Mitchell, M., and Watanabe, S.: Pulmonary pathophysiol-ogy in cystic fibrosis. Amer. Rev. Resp. Dis., 94:430, 1966.

5. Mellins, R. B., Levine, 0. R., Ingram, R. H., Jr., and Fishman, A. P.: Obstructive disease

of the airways in cystic fibrosis. PEDIATRICS, 41:560, 1968.

6. Engstrom, I., Karlberg, P., and Swarts, C. L.: Respiratory studies in Children. IX. Rela-tionships between mechanical properties of the lungs, lung volumes and ventilatory ca-pacity in healthy children 7-iS years of age. Acta Pediat. ( Stockh.), 51 :68, 1962. 7. Hyatt, R. E. : Dynamic lung volumes. In Fenn,

W. 0., and Rahn, H., ed: Handbook of Physiology, Sect. 3 Vol. 2, Respiration. Washington, D.C.: American Physiological Society, Chapter 54, 1965.

8. Macklem, P. T., and Mead, J.: Resistance of central and peripheral airways measured by a retrograde catheter. J. Appl. Physiol., 22:395, 1967.

9. Bodian, M.: Fibrocystic disease of the pan-creas. London: William Heinemann Medical Books Ltd., 1952.

10. Andersen, D.: Pathological anatomy of the early changes. In McIntosh, R., ed.: Re-search in Cystic Fibrosis. Transactions of the International Research Conference on Cystic Fibrosis. Washington, D.C., January 7-9, 1959.

11. Bowden, D. H., Fischer, V. W., and Wyatt,

J.

P.: Cor pulmonale in cystic fibrosis. Amer.

J.

Med., 38:226, 1965.

12. Macklem, P. T., Fraser, R. C., and Brown, W. C.: Bronchial pressure measurements in em-physema and bronchitis.

J.

Clin. Invest., 44:897, 1965.

13. Obstructive disease of the airways. New Eng.

J.

Med., 278:1398, 1968.

14. Avery, M. E., Calina, M., and Nachman, R.: Mist therapy. PEDIATRIcs, 39:160, 1967. 15. Waring, W. W., Brunt, C. H., and Hilman, B.

C.: Mucoid impaction of the bronchi in cys-tic fibrosis. PEDIATRICS, 39:166, 1967. 16. Hogg,

J.

C., Macklem, P. T., and Thuribeck,

W. M.: The site and nature of airway ob-struction in chronic obstructive lung disease. New Eng. J. Med., 278:1355, 1968. 17. Bates, D. V., and Christie, R. V.: Respiratory

function in disease. Philadelphia and Lon-don: W. B. Saunders, 1964.

18. Peters,

J.

M., Mead, J., and Van Ganse, W. F.: A simple flow-volume device for measuring ventilatory function in the field. Amer. Rev. Resp. Dis., 99:617, 1969.

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1969;44;315

Pediatrics

Robert B. Mellins