Small Airways and Interstitial Pulmonary Disease

COMMENTARY

Small

This

Airways

commentary

and

provides

Interstitial

editorial

perspectives

on the

report

which

follows

Pulmonary

Disease

T

he

concept

of disease

introduced

in

of the

1968

by

small

Hogg

airways

and

was

associates.1

These workers defined the site and nature of obstruction of the airways in chronic obstructive pulmonary disease ( COPD ) at the small airways. Morphologically, small ( less than 2 mm ) airways were narrowed or obliterated by inflammation, mucus, or fibrosis. The concept of two components to disease of the small airways was introduced by them, ie, a reversible or mucous due

component plugging

to fibrosis,

ation

of

small

due and an

to acute irreversible

distortion,

and

airways.

These

ly

support

that

airway

the

it is likely

of

alveolar

a distal

septae4

chronic

been

initiated,

the

for

Ostrow

and

of

small

of

unclear;3’4 disease

con-

disrup-

by

evidence airways.

of increased

narrowed

function

of interstitial

had

logic

features,

interstitial

heterogeneous

and

as COPD tilatory volumes, sically

cause

characterized

pulmonary

order

morphologic

of the 470

and

small

observations

airways

FULMER, ROBERTS

is not

clas-

defect

compliance)

to

disease

airflow.6

Be-

defect recent indicate

limited

tissues the con-

in this disphysiologic that

to COPD

disease

and

resistance

20

correlation

small two

made

pulmonary

( interstitial

collagen

of

to be

that

shown

morphologic

from pulmonary vascular

cryoglobulinemia) alterations consistent

can

studies inthis .

that

other

changes

idiopathic disease

that

involve

can dedisease. diseases

can

be

pulmonary

fibro-

associated

with

diseases

may with

useful

idiopathic

that

that physiologic of. small .airways have

of narbiopsy

dynamic cornflow-volume

ie,

disease

17

a good

considered

expiratory a

of

( 94 perinflammation of these

Furthermore,

demonstrated is

18

pulmonary

Seventeen

disease,

maximum

studies

of

between the finding in the specimens from studies

airways and the function

specific

12

study

indistinguishable

mixed logic

had

pulmonary

fibrosis or (71 percent)

small-airway

fibrosis

Subsequent

sis

some in small

study

obtaining testing

airways.12

was seen airways

and

by

patients.12

small

Our

pulmonary

small fine

to airflow

detailed

same

physiologic of

pliance curves.

that

disease

correlative was

the

narrowed

detectors

in

of 29 patients with idiopathic found small airways to be patients (70 percent). A detailed

cent) had peribronchiolar or bronchiolitis, and

and

found

pulmonary

performing in

rowed

and

groups

were

was made subsequently

we

29 patients

with

is characterized

of the supporting interstitium,6

of a restrictive ventilatory is easy to accept. However,

cept

has

a restrictive

obstruction

morphologically by fibrosis of lung, primarily alveolar

and

disease

volumes of

are

causes.#{176} Just

by an obstructive yenor increased pulmonary by

pulmonary interstitial

of

pulmonary

evidence

diseases

a variety

is characterized normal

( reduced

of common cmand morpho-

pulmonary

have

defect with interstitial been

without

because physiologic,

in

and

functional

disease

disease

Cherniack9

physiologic-morphologic tissue

Al-

pulmonary

Both

patho-

that

a study fibrosis

pulmonary

proteases may result in degradation of and subsequent emphysema.5 In contrast to its occurrence in COPD, disease of the small airways was not considered to be a part

recently.

In

Carnngton,8

alveolar

suggestion

interstitial

on

placed

disease. Exinterstitial

and on

airway

al.b0

with

elastin

until

The

et

Yernalt

Liebow

acute by

communicabeen

concentrated

patients

neutrophilic

though grouped together ical, roentgenographic,

macrophagic

by

interstitial

pulmonary obliterans

by

small

1973

original

“bronchiolitis have

in

emphasis

described

interstitial

these

disease

the

in

or

pulmonary

of

cept

their

in interstitial

with

mechanical

release

airways

in has

consistent

to the development of Once this last process

and

alveolitis.

small

Rich7

recently

alterations

role

airway

only

suggested

is

and

and

tion,

pathophysiologic

evident

of small airways in fibrosis was mentioned

abnormalities.

emphysema, small

Hamman

and be

narrowing pulmonary

logic

development

of air

Although idiopathic

may

or obliterbe one of the data strong-

The

morphologic

COPD disease.

reports

eventual

that

to trapping

tributes

has

in

particularly

however, tion

suggestion.24

disease

COPD,

may current

of the of

most

findings

that disease of the small airways earliest changes in COPD, and

many

pneumonia”

inflammation component

narrowing

that

features pulmonary

also disease

and

essential

have physioof the small

airways. 5

CHEST, 77: 4, APRIL, 1980

Granulomatous

interstitial

airways. such

graulomata

with

in

patients

disease Young and associan involvement by

pulmonary

may also involve small ates16 in 1967 demonstrated

sarcoidosis.

Although

evidence of chronic obstruction of airflow an increased residual volume and normal or normal total lung capacity. #{176}’31 Roentgeno-

tional

with near

graphically,

these workers noted no evidence of obstruction to airflow on simple spirometric testing, this publicalion preceded our current concepts of the relative insensitivity of this test to mild degrees of obstruclion to airflow. Subsequent studies have shown that granulomata can involve small airways and that patients with sarcoidosis can have physiologic alter-

coexisting

ations

ease,

consistent

with

disease

of

the

small

air-

20

At least

three

terstitial

occupational or environmental in( hypersensitivity pneumonitis,

diseases

asbestosis,

and

coal

dust

disease)

have

been

shown

chronic

both

morphologic

Simicoal dust the small

many

Although

its

occurrence

small

studies

in

airway

susceptibility

now demonstrated pulmonary disease,

not

always

interstitial

disease

which suggests its occurrence. of the disease

have is

that several factors These factors might process, chronicity of the

host,

and

certain

tal factors.6’12’26’27 The functional disease of the small airways is also it is likely

that

small

airway

present,2 27

must determine include severity of the disease,

disease

environmen-

of

significance

variable. is the

While

earliest

significance of small airway disease in interstitial pulmonary disease is speculative. It is likely that disease of the small airways contributes to the ventilation-perfusion mismatching in interstitial pulmonary disease and hence to the hypoxemia of this disease.6’2 In addition, small airway disease may be partly refunctional

alteration

sponsible

for

pulmonary

in

alterations

volumes4

in for

the

COPD,

pulmonary

example,

recoil trapping

and of

air

may mask the effects of alveolar fibrosis. Perhaps this is why pulmonary volumes correlate poorly or not at all with the severity of fibrosis in interstitial pulmonary fibrosis and in many of the inorganic dust diseases. ’ Disease of the small airways may also contribute to the development of chronic obstruction of airflow in interstitial pulmonary disease. Indeed,

it

is well

documented

but

poorly

recog-

nized that some patients with interstitial pulmonary disease progress to show a pattern of chronic obstruction of airflow. The most notable example is chronic sarcoidosis, in which there may be func-

CHEST, 77: 4, APRIL, 1980

of

fibrosis

with

hyperinflation.3’

sies

Simi-

which

473),

with progressed

had

evidence

showed

an

active

bronchiolitis patients

of

airways.

and

ob-

and

as-

idiopathic

restrictive spirometric

in small

of dis-

to the

McCarthy

patients rapidly

both

there

airways

contribute

initially had normal timed

an obliterative Both

Although

of obstruction pulmonary

of small

probably

two

to airflow in each

lung.M

( see page

fibrosis

addition,

tance

of

mechanism of interstitial

narrowing

recoil

Both patients defects (with

brosis.

airways.23

areas

and

X

intrinsic

In this issue sociates describe

in

the

histiocytosis

loss of elastic tructi618

persensitivity

is

dense

are scant data on the airflow in these forms

monary

pneumonitis,

are lesions

larly, chronic obstruction of airflow may be present in patients with chronic hypersensitivity pneumonitis,m some of the inorganic dust diseases,tm and

to have physiologic alterations consistent with disease of the small airways.2123 A bronchiolo-alveolitis, the characteristic morphologic finding of hyequivalent of such functional abnormalities. larly, the early morphologic change of disease is the coal macula which involves

there cystic

pul-

to COPD.

ventilatory data), but, increased

resis-

Pulmonary

biop-

alveolitis

and

either

or endobronchiolar

were

fi-

treated with corticosteSix to 12 months later,

roids and improved initially. both had physiologic, clinical, and radiographic findings typical of COPD. Pressure-flow studies indicated that a reduction in flow during maximum expiration was due mainly to reduced elastic recoil and increased dynamic compression. These data would be consistent with emphysema. The report of McCarthy et a! and the data cited in this editorial strongly support the concept that there are distinclive similarities between the interstitial and obstructive

pulmonary

diseases.

The

report

by McCarthy

et

al also raises questions on the possibility of acute interstitial injury as a cause for COPD. It is well documented that acute bronchiolar injury can lead to COPD, for example, that resulting from acute inhalation of smoke.36 Could an acute viral alveolitis and bronchiolitis or subclinical idiopathic pulmonary fibrosis do the same? Current data suggest that lobar emphysema is associated with acute viral pneumonias.37 Certainly, influenza can be associated with physiologic alterations consistent with disease of the small airways. This type of injury in the susceptible person may lead to classic COPD or to chronic obstructive disease of the small airways, as described by Macidem and colleagues.39 Recently, Miller et al’#{176} suggested that sarcoidosis may

The raises Ostrow

ment

cause

diffuse

report important and

in the

bullous

by

emphysema.

McCarthy therapeutic

Cherniack9

physiologic

and

and associates also questions. Whereas we12

observed

abnormalities

improve-

of small

SMALL AIRWAYS AND INTERSTITIAL PULMONARY DISEASE

air471

ways

on

treatment of McCarthy

patients pulmonary

This

disease

suggests

versibly

with corticosteroids, et al developed despite

that

corticosteroid

most

damaged,

small

perhaps

with have

ess?

Of

importance

the

overall

interstitial

be

greater

significance

actively

of

knowledge

distinction

diseases

of them

Could

synthesis, the disease

secreproc-

question

airway

we

of

less

the “indiseases.

these distinct

two as

our

increases. Jack

D. Fulmer,

M.D.,

F.C.C.P.*

Birmingham,

and

in

should

alveolar

repair in both pulmonary

between

of

disease

Clearly,

becomes

irre-

fibrosis.

mechanisms

injury and “obstructive”

functional

classes

were

is the

disease.

investigating

and bronchiolar terstitial” and

The

collagen altered of small

pulmonary

treatment.

airways with

agents that interfere lion, or cross-linking even

the two obstructive

William

C. Roberts,

M.D.,

Ala

Md

#{176}Veterans Administration Medical Center and Department of Medicine, University of Alabama. #{176}Pathology Branch, National Heart, Lung, and Blood Institute. Reprint requests: Dr. Fulmer, Department of Medicine (Putmot3ary), University of Alabama Medical Center, Binningham 35294 REFERENCES

1 Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278:1355-60. 2 Cosio M, Ghezzo H, Hogg JC, et al. The relations between structural changes in small airways and pulmonary function tests. N Engl J Med 1977; 298:1277-81. 3 Thurlbeck WM. Changes in lung structure. In: Macklem PT, Permutt 5, eds. The lung in the transition between health and disease. New York: Marcel Dekker, Inc, 1979:17-41. 4 Macklem PT. Changes in lung mechanics: pressure-volume and pressure-flow relations. In: Macklem PT, Permutt 5, eds. The lung in the transition between health and disease. New York: Marcel Dekker, mc, 1979:53-71. 5 Kuhn C, Senior RM. The role of elastases in the development of emphysema. Lung 1978; 155:185-97. 6 Fulmer JD, Crystal RG. Interstitial lung diseases. In Simmons DE, ed. Current pulmonology. Boston: Houghton Mi.fflin Professional Publishers, 1979; 1: 1-65. 7 Haminan L, Rich AR. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 1944; 74:177-212. 8 Liebow AA, Carrington CB. Alveolar diseases: the interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of Pulmonary Radiology. New York: Grune and Stratton, Inc, 1967: 102-41. 9 Ostrow D, Cherniack RM. Resistance to airflow in patients with diffuse interstitial lung disease. Am Rev Respir Dis 1973; 108:205-10. 10 Yernalt JC, Dejoinghe M, DeCoster A, et al. Pulmonary mechanics in diffuse fibrosing alveolitis. Bull Physicpathol Respir 1975; 11:231-44. 11 Roberts WC. Histologic observations in idiopathic pul.

FULMER, ROBERTS

1977;

20:1071-9.

14 Wohlgelernter D, Loke J, Matthay BA, et al. Systemic and discoid lupus erythematosis: analysis of pulmonary function. Yale J Biol Med 1978; 51:157-64. 15 Bombardieri 5, Paoletti P, Fern C, et aL Lung involvement in essential mixed cryoglobulinemia. Am J Med 1979; 66:748-55. 16 Young RC Jr, Carr C, Shelton TG, et aL Sarcoidosis: relationship between changes in lung structure and function. Am Rev Respir Dis 1967; 95:224-38. 17

F.C.C.P.#{176}#{176} Bethesdtz,

472

monary fibrosis. (pp 773-776). In: Crystal RG (moderator). Idiopathic pulmonary fibrosis: clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med 1976; 85:769-88. 12 Fulmer JD, Roberts WC, Von gal ER, et al. Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations. J Clin Invest 1977; 60:595-610. 13 Guttadauria M, Ellman H, Emmanuel G, et aL Pulmonary function in scieroderma. Arthritis Rheumatism

Young

BC

trypsin

levels

tivity.

Chest

Jr,

Headings

VE,

in sarcoidosis 1973;

Bose

5,

: relationship

et

al.

Alpha-i

to disease

antiac-

64:39-45.

18 Kaneko K, Sharma OP. Airway obstruction in pulmonary sarcoidosis. Bull Eur Physiopathol Respir 1977; 13:23140. 19 Levinson RS, Metzger LF, Stanley NN, et al. Airway function in sarcoidosis. Am J Med 1977; 62:51-9. 20 Carrington CB, Gaensler EA, Mikus JP, et aL Structure and function in sarcoidosis. NY Acad Sci 1976; 278: 265-83. 21 Allen DH, Williams CV, Woolcock AJ. Bird breeders’ hypersensitivity pneumonitis: progress studies of lung function after cessation of exposure to the provoking antigen. Am Rev Respir Dis 1976; 114:555-66. 22 Jodoin C, Gibbs GW, Macklem PT, et al. Early effeots of asbestos exposure on lung function. Am Rev Respir Dis 1971; 104:525-35. 23 Seaton A, Lapp NL, Morgan WKC. Lung mechanics and frequency dependence of compliance in coal miners. J Clin Invest 1972; 51:1203-11. 24 Seal RME, Hapke EJ, Thomas GO, et al. The pathology of the acute and chronic stages of farmers lung. Thorax 1968; 23:469-89. 25 Schofield NM, Davies RJ, Cameron IR, et al. Small airways in fibrosing alveolitis. Am Rev Respir Dis 1976; 113:729-35. 26 DeTroyer A, Yernalt JC, Dierekx P, et al. Lung and airways mechanics in early pulmonary sarcoidosis. Bull Eur Physiopathol Respir 1978; 14:299-310. 27 Bjerke 1W, Tashkin DP, Clements DJ, et aL Small airways in progressive systemic sclerosis. Am J Med 1979; 66:201-9. 28 Fulmer JD, Roberts WC, Von Gal ER, et al. Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis. J Clin Invest 1979; 63:665-76. 29 Gaensler EA, Carrington CB, Coutu RE, et aL Radiographic physiologic-pathologic correlates in interstitial pneumonias. Prog Respir Res 1975; 8:223-41. 30 Miller A, Teirstein AS, Jackler I, et aL Airway function in chronic pulmonary sarcoidosis with fibrosis. Am Rev Respir Dis 1974; 109:179-89. 31 DeRemee BA, Andersen HA. Sarcoidosis: a correlation

of

dyspnea

tion

32

Braun

with

changes.

SR,

radiographic

Mayo Clin Proc doPico GA, Tsiatis

stage

and

pulmonary

1974; 49:742-5. A, et a!. Farmer’s

func-

lung

CHEST, 77: 4, APRIL 1980

disease:

Rev

clinical

long-term

physiologic

and

outcome.

Am

1979; 119:185-91. 33 Morgan WKC, Seaton A. Occupational lung diseases. Philadelphia: WB Saunders Co, 1975: 132-4, 174-92. 34 Basset F, Corrin B, Spence H, et al. Pulmonary histiocytosis X. Am Rev Respir Dis 1978; 118:811-20. 35 Leaver DG, Tattersfield AE, Pride NB. Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. J Clin Invest 1973; 52:2117-34. 36 Kirkpatrick MB, Bass JB. Severe obstructive lung disease after smoke inhalation. Chest 1979; 76:108-10. Respir

Chronic

Obstructive

following

Idiopathic

D. S. McCarthy, E.

S.

M.D.,

development

fibrosis

bronchioles.1 patients

process involves et

this

a!2

M.D.,

lung

evidence

of

as that

reported had

see page

pulmowell

as 17

the

of

pathologic

18 and

470

bronchiolar

disease.

Other

authors idiopathic

have reported small airways disease in pulmonary fibrosis3 and other idiopathic disease involving the lung parenchyma such as pulmonary sarcoidosis4’5 and progressive systemic sclerosis.6’7 This report describes the rapid development of irreversible airflow obstruction in two middle-aged nonsmoking

women

who

and radiologically from fibrosis ( Hamman-Rich CASE CASE

recovered

clinically

acute idiopathic disease).

had

pulmonary

REPORTS

1

A 58-year1ld an eight-week From

the

housewife was admitted to the hospital history of progressive cough productive Respiratory

of Manitoba, #{176}#{176}Associate Professor. University

tAssistant Manuscript

Professor. received

May

74:167-77.

MT. The sarcoidosis:

AS, Chuang in pulmonary

stages

and

to

response

of

sequence correlation therapy.

Mt

44:852-65.

F.C.C.P.;t

obstruction

idiopathic

alveoli

diagnosis

For commentary, physiologic

1971;

Miller A, Teirstein physiologic changes with radiographic Sinai J Med 1977;

40

Fibrosis*

airflow

in

the

Fulmer with

39

F.C.C.P.#{176}#{176}

of irreversible

inflammatory

nary

38

Pulmonary

two nonsmoking women who recovered from acute Idiopathic pulmonary fibrosis is discussed. Pulmonary fibrosis was diagnosed clinically and by lung biopsy. Recovery both dilnicaDy and radiologically was complete. Several pulmonary function studies in both patients showed a typical restrictive pattern (reduced

he

BC,

Disease

In

T

Fraser

Philadelphia:

Pulmonary

M.D.;#{176}#{176} D. N. Ostrow,

Hershfield,

The rapid

Pare j s.p. Diagnosis of diseases of the chest WB Saunders Co, 1979; 3:1431. Little JW, Hall WJ, Douglas BC, et al. Amantadine effeet on peripheral airways abnormalities in influenza. Ann Intern Med 1976; 85:177-82. Maddem PT, Thurlbeck WM, Fraser BC. Chronic obstructive disease of small airways. Ann Intern Med

37

Dis

Section, Department Winnipeg, Manitoba, 10;

CHEST, 77: 4, APRIL, 1980

revision

accepted

with of 3

of Medicine, Canada. June

27.

normal

volumes

and

FEV1/FVC

tients exhibited (hyperinflation, ments). These

dioxide

carbon ratio).

Within

diffusing

one

year

capacity, both pa-

an obstructive pattern of dysfunction gas trapping, reduced airflow measurepatients illustrated Irreversible airway

obstruction following recovery of pulmonary fibrosis.

from

the

restrictive

stage

cup mucopurulent sputum per day, feverishness and increasing shortness of breath and fatigue with a weight loss of 3.5 kg. There was no history of chest pain, wheezing, swelling of anides or joints. Past history was non-contributory. The patient did not smoke, had no allergies, and had been a housewife all her adult life. There was no known exposure o noxious inhalants. On physical examination, the patient was found to be of average nutrition, temperature 38.8#{176}C,pulse rate 108, respirations 24/rain, blood pressure 110/70 mm Hg. The trachea was deviated to the right; there was no clubbing of digits. Chest movements and air entry were diminished over the right lung, and there was dullness to percussion and increased tactile vocal fremitus on the right side. Mid and late inspiratory crackles were present over both lungs, especially the lower lobes. No clinical evidence of airways obstruction was found. Other systems were normal. The roentgenogram taken on admission showed bilateral lung infitrations, especially on the right side. A chest film had been taken 15 months earlier because of unrelated problems but showed normal findings. Because of difficulty in establishing a diagnosis, lung biopsy was performed through a small right thoracotomy. On inspection the lung was unremarkable and a biopsy was taken from the right upper lobe. The biopsy revealed diffuse disease with interstitial fibrosis and pronounced epithelial hyperplasia of the alveolar walls. There were numerous subepithelial collections of foamy macrophages and many free alveolar phagocytes ( Fig 1A). Several wide bands of fibrosis were seen and vascular sclerosis was pronounced. The respiratory bronchioli showed changes of obliterative bronchiolitis (Fig 1B). No granulomath were seen.

The

patient

was

treated

with

antibiotics,

but showed

COPD FOLLOWING IDIOPATHIC PULMONARY FIBROSIS

no

473