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 presentcon-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 associatedvithi 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
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.
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.
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.
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
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
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.
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