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DIAGNOSIS OF CYSTIC FIBROSIS OF THE PANCREAS

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(1)

AMERICAN

ACADEMY

OF

PEDIATRICS

PROCEEDINGS

DIAGNOSIS

OF

CYSTIC

FIBROSIS

OF

THE

PANCREAS

Giulio J. Barbero, M.D.

iIW Children ‘S Hospital of Philadelphia, and Department of Pediatrics. University of Pen imsi,!rania

Presemited as part of a Symrmposium on Cystic Fibrosis of the Pancreas at the Annual Meeting of the

Amiierican Academy of Pediatrics, October 1958.

ADDRESS: 1740 Bainbridge Street, Philadelphia, Pennsylvania.

Pediatrics

VOLUME 24 OCTOBER 1959 NuIBr,n 4

T

PAPER is a (!isCussiOfl of present

con-cepts imi d!iagnosis of cystic fibrosis of

the I)tncnea5. Such concepts should d!evelop

from an examination of the definition of

this disease. Cystic fibrosis is now known as

a d!isease which appears as focal

involve-fluent of various exocnine glands in the

body, with its principal symptomatic

mani-festations in two miiain anatomic areas. These two areas are the gastrointestinal tract where symptoms are exhibited as more

frequent, foul-smelling and l)tilky stools,

and the respiratory tract where involvement

is shown principally as cough, wheezing or

respiratory distress.

PARTICULAR CLINICAL FEATURES

My Pt1rP5e here is not to discuss the

wehl-recogmiized picture, but rather to

em-phasize some of the clinical characteristics. The clinical picture has widened in its

range because of improved diagnostic tests

such as determination of electrolytes in

sweat amid greater awareness by physicians.

As a result, there are now known to be pa-tients who show more or less gastrointesti-nal or respiratory involvement. On the one

hand, there is am#{238}emilanging group of

ii;t-tients who have rimici;i1iy respiratory

in-volvement and ‘er’ little gastrointestinal

d!isond!er. These l)atiemits, of cotmrse, are

fre-(Itmently confumsed with pttients with other

chronic pulmonary disease or asthma. On

the other hand, there is now a small groump

of latients vithi gastrointestinal sym)tOni5

and very’ little respinator’ disease. These

patients often are confused with those

ha-ing chronic (harnlica 01’ cehiac disease.

There are a few points whichi miiighit be

emiiphasized as clinically diagnostic

chiarac-teristics.

Cystic fibrosis is often associated

vithi the diarrhea! grotip of diseases, but it

is miot truly a diannheal disease in the sense

of more fluid bowel mnovemnents with acute

exacenbatiomis. The stools are bulky,

foul-smelling and! immifonnied movements, usually

passed! three to four times a d!ay’. A ‘en’

large appetite has been constantly

eflul)hia-sized, hut among a large enotmghi group of

such children OflC is impressed that this is

not a constant sym)tom. \Ve have lioticed!

a fairly consistent enlargement of the

sub-maxillary salivary gland in over 50% of

(2)

PrhtPse of the rectum in the pediatric groump. The prolapse often is improved by

adlequate 1)tflcreatic sumbstitution therapy.

The classical findings of respiratory (liS-ease are: ern1)hysema, with widening in the antero-postenior dliamneten of the thorax;

sticky rales amid! wheezing in the hmngs; and!

cluI)l)ing of the fingers. In its earliest form

the clubbimig usually appears as a swelling

jtist proximal to the nail over the nail bed.

The copious v:scid secretions imi the

re-5PinatrY tract cause the resp:natory

symp-toms and are the major problem of cystic fibrosis. These children with advanced forms of cystic fibrosis are literally stmffo-cated by these secretions. Figure 1 shows

how copioums these secretiomis cami be, as

seen in looking down into the larynx at

necropsv of a patient with cystic fibrosis.

Actually this disease is not really a bron-chiectatic disease, but rather a situmation of

intraluminal secretory obstruiction,

ulti-mately progressing to secondary

bronchi-ectasis in the advanced stages of disease. Figure 2 shows the emphysematoums lungs, trenmendously ballooned oumt with patchy areas of atelectasis. Figure 3, a

cross-see-tion of a gross specimen of lung, shows the copious mucopurulent secretion exuding from the bronchioles, which produces such

a complete obstruction to air passage to the

alveoli. Finally, in histologic examination of bronchioles, one sees a polysaccharide-staining envelope of secretory material,

in-to be helpful.

In the noemitgemiogramii of tile lumngs an early sign may be atelectasis of one lobe.

Hyperaerated himng fields, where all the films are good inspiratory films, with or withoumt atelectasis of one lobe, raises the )ossihihity of cystic fibrosis. Figure 4 shows

atelectasis of the right middle lobe in

hy-peraerated lungs, as an example. Later in the disease a characteristic appearance de-velops in the lumngs in cystic fibrosis (Fig. 5). There is an increase in luing markings, de-pression of the diaphragm, an increase in

anterior-sumpeni( )r miiecliastinal air, amid

wid-ening of the antero-postenior diameter of the thorax. Often this appearance is con-fumsed vith mniliarv tuberculosis or some

other emphysematoims or asthmatic state. Findings from the throat culture, al-though not diagnostic, have one relatively consistent aspect: in the earlier stages of the disease, there tends to be hemolytic coaguilase-positive staphylococci in the

re-spiratory tract in a very high percentage of

the cases. Later, after intensive antibiotic therapy, there often is an invasion of resist-ant organisms, such as pseumdomonas or pro-teus. Cultures from the throat can he useftml in the initial study and follow-imp of these patients.

(3)

660 DIAGNOSIS OF CYSTIC FIBROSIS

I

Fic. 1 (Upper). View into larynx at necropsy of child with cystic fibrosis. Copious mucopurulent secre-tion fills the laryngeal lumen.

(4)

A

‘F

ib 4’

0 PFumALHIcs, 23:7:31, 1959 errattmmn, 23:8:36.

1959,

Fm;. :3, Cut section of lung at necropsy of child who (lied froni Cystic fibrosis, showing extensiv(’

millmCI)ptmnlmleflt secretiomis exuclimig fromn bromichioles.

niarked d!eficiencv of ptncreitic emizvmes iii

the duodlemial fluid.

The screening tests for elevated chloride

in sweat are based on the fact that a

cer-tam comicentration of silver nitrate will

re-act with a centaimi level of chloride in the

s’(lt to forni silver chlonkie which is

visi-l)Ie On ami indicator background of brick-ned

l)t15iltmm dichinomnate. The screemiing test

thiat has received! greatest umse is the

agar-I)lctte test of Siiwachmiian. A finger pnimit On

dli agar I)late after a few secomids appears

as a yellowish-white color chamige on the

red colOredi l)latc ‘hien time chloride is

ele-‘ate(l. The imprint is graded as 1 +

,

2+ , on

:3 + , with the mrare intense 3 + being

indica-tive of au elevated chloride in the sweat

(Fig. 6). The problem with this test is that it is often difficult to interpret, particularly in the imitermediate area of response. In

skilled hands of physicians with

consider-tble experience with the test, it appears to hat’ somiu’ scm’cemiiiig ‘alue: bmt imi tIit’

hands of individuals who do not see a

great number of children with cystic

fibro-sis, there is always the problem of interpre-tation that makes for frequent confuision.

Another screening test is the test devel-oped by \Vebb of Toronto, Canadla. This

test employs a piece of filter paper that is

initially saturated! with 2% silver nitrate so-luition. The thumb amid forefinger are

proxi-mated on both sides of the paper in one

area for a few secon!s, following which

the paper is satuirated with pot1ssium

di-chromate solution (Fig. 7). This test may

be a little better than the agar-plate type in

one respect, becauise it certainly gives

posi-tive anc! negative responses; however, the

difference is not that great from that of the

agar plate. Again, it muist he emphasized

that it is a screening test.

(5)

662 DIAGNOSIS OF CYSTIC FIBROSIS

.#{232}:

. ?‘#{149},

r

.1’

/

Fir.. 4 (Upper). LLmmmg fields of 4-year-old girl with proven cystic fibrosiS, showing atelectasis amid

extremmie hvperaeration of limngs lwst slmowmm by the imicreased amitero-posterior diamucter in tIme lateral view.

Fic. 5 (Lower). Lung fields of 4-year-old boy with proven cystic fibrosis, slmovimmg typical hvperaerated lmmngs am d (agg(’rIte(l limmmg mmmmrkings vith sfX)tted smmmallmreas of h’mmitv immtime J)(’riplm(’rv.

This iatcIl of film is muade b’ Eastmnati

Ko-dak with silver nitrate and p0t155itmmn

di-chrornate conul)ined in the emulsion. The

patch is tal)e(i to the vaslwd l)t1ni of the

hand with clear i)liStid tape. A small

plas-tic bag is placed over tlit’ hand amid the

patch is allowed to stay in place for 20

miii-utes. 1mmthe negative test there is almost no

change in the initial color of the film patch.

1’he positive test shows considerable color

babies do miot sweat proftmselv, and one

usu-ally sees d!roplets of sweat onl’ abouit the

forehead. Such a fihni 1mtch can be easily

applied! to the forehead of arm imifant.

There are i few precatmtions about all

these screening tests. \Vashumig tile hands

may be important. From surveys with these

tests, it seems the children often manage to

get sommiething salty oh their hands, which

(6)

l’m(;. 6. Shwachman agar-plate test showing grading in intensity of elevated

chloride in the sweat.

as diagnostic interpretive tests. They were not intended! l)\’ them initial investigators to be d!efinitive tests and should not be so

used. Like all screening tests they have a

lower incidence of false negatives and a huigher incid!emice of bond!erhimie and false

Positive respomises, vhich will require

fur-then study 1)’ the classic sweat collection methods.

Another screening test is that based! on

stool trypsin exanuination. There is an en-hanging group of children with cystic

fibro-sis who have normal pancreatic function or

only partial pancreatic insufficiency. This group, along with other factors leading to false interpnetatiomis, has made most

experi-enced persons conclude that this

examina-tion has the least reliability of all the screening examinations. With the

avail-ability of screening tests based on the

chloride in sweat, this stool test should have

only minimal usefulness.

The definitive sweat tests all imivolve the collection of sweat under either thermal or cholinergic chemical stimulatiomi. The umsual method has been to place on the back of the body a gauze patch covered with an

im-peniiieable plastic niatenial and sealed off

with adhesive tape. The child is drapped in plastic sheeting and blankets for thermal

stimulation. In abouit 30 niinutes the gauize

patch, which had been previously weighed, is removed and reweighed. The sodiumm or chloride is then extracted and determined.

Another method we have used is to wrap the child in a plastic sheet, or put babies in an Isolette#{174} incubator, preheated to 95#{176}F, for about a half hotmr. The droplets of sweat are then sucked up with a tuberculin

syr-inge or dropper. The sodium or chloride is directly determined in the sweat with-out any intermediate steps such as the

(7)

I

V

Fmc. 7. \\‘el)I) test, showing positive test Ofl left (clear circimlar area in center of dark stained

regiomi) dIXI 1negative test omm the right.

664 DIAGNOSIS OF CYSTIC FIBROSIS

There is t serious caution to be emii)hOyed in these thermal stimimlating tests. A small Iiummiil)er of childiren have been reported to have died froni sudden acute heat

collapse during the procedure. This heat

collapse 1I)I)e1rt(! particularly iii vounig

babies viio were inalnoimnishied. Therefore,

I)()1)I hydration, a(leqlmate salt imitake and avOi(!aflce of prolonged heating stinitmlums,

are of real imnl)ortaiice in preventimig this

senioums catastrophe.

Recently tests 1)ased! on cholinergic chem-ical stimulation, using local injection of

mecholyl either intnadermally or by

ionto-phoresis, have been reported.#{176} Here a

weighed gauize 1)atch or filter paper d!isk

has been utilized for sweat collection as in

the thenmimal stimi mu latioii mnethiods. This ty1)e

of mimethmod mmiav i(’Ct’iV(’ miiore attt’mmtioii in

the futumre because of the d!aLger of the

vhiole l)Ody heat stiniulatiomi techinique.

The main thiimig to emiiphiasize vithi all

these miiethod!s is thiat anvomie shiouik!

dc-velop his OWn exl)erience with a givemi tech-niqume so that the l)rollemiis are umn(lenstOod!

and confidence iii the ramige of variability of tl 1)ctrtictmlclr nietiiod is attained.

Tahle I is a stmmiimiiatiomi of tile niajonitv of

Pumlhisled! studies iii the Eunopeami ami(l

Amenicai literature on the sveat test. The

difference jU the miieamis for sodiuimii in sweat

of 28 meq/l imi the control children anti

117.9 meq/l for child!ren vitii cystic

fibro-sis is quite striking. For chloride a similar

situation holds with sweat from the control

children having a miiean of 24.8 ineq/l amid

childnemi with cystic fibrosis, 120.9 mneq/i.

(8)

sum-that the different methods umsed! in

collect-ing sweat do make some difference iii

de-fining the borderline level that is indicative

of a diagmiostic elevation of 50d!iumfli and!

chloride in sweat.

At the present time the sweat test has

been about 98-99% accurate in the diagnosis

of cystic fibrosis. Sodiumm in sweat above 80

meq/l is definitive with all the methods

which have been reported!, in a situation

where some of the clinical featumres of this

disease exist. The level of sodium

concen-tration considered diagnostic for cystic

fi-brosis has been set as somewhere above

50-80 meq/l, the actumal diagnostic level in

this range being d!ifferent with the vanioums methods of collection. There are a few cases being discovered! in vanioums clinics with

normal sweat tests, i.e., a sweat test that reveals less than 50 meq/l for sod!iumm or

chloride. Babies umnden 6 weeks of age do

not sweat profusely so that generally it is

probably better to wait until 3 months of

age for definitive examination.

Prior to the sweat test there was no qules-tion that the examination of the duodenal

fluid for pamicreatic enzymes was the

defini-tive diagnostic technique. Of the various pancreatic enzymes (trypsin, amylase and hipase), dietermination of trypsin was con-sidered the most reliable. Later, cases with normal pancreatic enzymes, or only partial

decrease of pancreatic enzymes, particularly

in the early course of the disease were re-ported. These cases were considered to have partial pancreatic insufficiency, and

gener-in

the rare case where there is a classic pictumne

of cystic fibrosis as diefined by respiratory

and! gastrointestinal symptoms, and yet nor#{149}

mal or borderline concentrations of sodiuim

and chloride in sweat are discovered. At any

rate, where available, intubation certainly

can he helpfully used!, since the diagnosis of

cystic fibrosis is an important one with

re-spect to its consequmence, and one that the

physician needs to be absoluitely sure of by

as many definitive objective laboratory

en-tenia as possible.

In summmany, we have tried to focuis your

attention Ofl the widening pictuine of cystic

fi-brosis, in which there is not always a clear

groump of classic manifestations. There are

some sPecial aspects of clinical features of

d!iagnostic value, suich as atelectasis of a

lobe of the luing, prolapse of the rectum, anc! biliary cirrhosis; all of these are being found with increasing frequency. The screening tests for electrolytes in sweat are

most meaningful as negative tests; however,

positive screening tests always carry the need for verification by the more exact

sweat collection techniques. Values for so-dium in sweat above 50 to 80 meq/l, de-pending umpon the different methods, are definitive and helpful in about 98 of the cases thus far studied. Duodenal intubation has its greatest use in cases with borderline sodium levels in sweat and especially in the rare cases where there is normal sodium and chloride in the sweat and suggestive clinical manifestations characteristic of

(9)

1959;24;658

Pediatrics

Giulio J. Barbero

DIAGNOSIS OF CYSTIC FIBROSIS OF THE PANCREAS

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(10)

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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