The Pathophysiology, Diagnosis, and Investigation of Cystic Fibrosis
Girish Sharma, MD, FCCP Associate Professor of Pediatrics and Director, Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center
Cystic Fibrosis
64
B USINESS BRIEFING: US RESPIRATORY CARE 2006
a report by
Girish Sharma, MD, FCCP
Associate Professor of Pediatrics and Director, Pediatric Pulmonology and Rush Cystic Fibrosis Center,
Rush University Medical Center
Cystic fibrosis (CF) is the most common lethal inherited
disease in Caucasian populations. CF is an autosomal
recessive disorder, and most carriers of the gene are
asymptomatic.The incidence is one in 3,200 in people
of Northern European origin, one in 15,000 in African-
Americans, one in 9,200 in Hispanics and one in 90,000
in Asian Americans. CF is a disease of exocrine gland
function, involving multiple organ systems and chiefly
resulting in chronic respiratory infections, pancreatic
enzyme insufficiency, and associated complications in
untreated patients. Pulmonary involvement occurs in
90% of patients surviving the neonatal period.End-stage
lung disease (ESLD) is the principal cause of death.
Pathophysiology
CF is caused by defects in the gene for CF trans-
membrane conductance regulator (CFTR), which
encodes to a protein that functions as a chloride
channel and is regulated by cyclic adenosine
monophosphate (cAMP). Mutations in the gene for
CFTR result in abnormalities of cAMP-regulated
chloride transport across epithelial cells on mucosal
surfaces. The failure of epithelial cells to conduct
chloride and the associated water transport abnor-
malities result in viscid secretions in the respiratory
tract, pancreas, gastrointestinal tract, sweat glands, and
other exocrine tissues. Increased viscosity of these
secretions makes them difficult to clear.
Pathophysiology of Lung Disease
Most fatalities associated with CF result from progressive
lung disease. For individuals with CF, the lungs are
normal in utero, at birth, and after birth, before the onset
of infection and inflammation (except, possibly, for the
presence of dilated submucosal gland ducts in the
airways). Shortly after birth, many patients with CF
acquire a lung infection, which incites an inflammatory
response.Infection becomes established with a distinctive
bacterial flora. A repeating cycle of infection and
neutrophilic inflammation develops.The neutrophils are
the key players in the pathophysiology of lung disease.
Cleavage of complement receptors CR1 and C3bi and
immunoglobulin G (IgG) by neutrophil elastase (NE)
results in failure of opsonophagocytosis, leading to
bacterial persistence. NE also causes production of the
neutrophil chemoattractant interleukin (IL)-8 from
epithelial cells and elastin degradation, and it acts as a
secretogogue, thereby contributing to persistence of
inflammation and infection,structural damage,impaired
gas exchange, and, ultimately, ESLD and early death.
Pathophysiology of
Gastrointestinal Disease
Defects in CFTR lead to reduced chloride secretion
with water following into the gut.This may result in
meconium ileus at birth and distal intestinal obstruction
syndrome (DIOS) later in life. In addition, other
pathological disorders complicate the simple
relationship between the apical chloride and water
secretion and the disease.The pancreatic insufficiency
(PI) decreases the absorption of intestinal contents.
Mechanical problems associated with inflammation,
scarring, and strictures may predispose the patient to
sludging of intestinal contents, leading to intestinal
obstruction by fecal impaction or to intussusception.
Adhesions may form, leading to complete obstruction
that may require resection, leading, in turn, to loss of
absorptive epithelium of the distal ileum.
Pathophysiology of Pancreatic Disease
As part of a normal digestion, stomach acid is
neutralized by pancreatic bicarbonate, leading to the
optimal pH for pancreatic enzyme action. Reduced
bicarbonate secretion in response to secretin
stimulation has been demonstrated in patients with CF;
both those with PI and those with pancreatic
sufficiency (PS). Reduced bicarbonate secretion affects
the digestion so that neither endogenous nor
exogenous pancreatic enzymes can work at their
optimal pH.
Other factors, such as reduction in water content of
secretions, precipitation of proteins, and plugging of
ductules and acini, prevent the pancreatic enzymes from
reaching the gut. Autodigestion of the pancreas
occasionally leads to pancreatitis. Most patients with CF
(90?95%) have pancreatic enzyme insufficiency and
The Pathophysiology, Diagnosis, and Investigation of Cystic Fibrosis
Girish Sharma, MD, FCCP, is Associate
Professor of Pediatrics and Director
of Pediatric Pulmonology and Rush
Cystic Fibrosis Center at Rush
University Medical Center. He is a
member of the American Thoracic
Society (ATS) and a fellow of the
American College of Chest Physicians
(ACCP). He is board-certified in
pediatrics and pediatric
pulmonology. Professor Sharma?s
special interests include pulmonary
problems in patients with
neuromuscular disorders and
patients with sickle cell disease,
cystic fibrosis (CF), pediatric asthma,
and novel techniques for lung
function testing in children,
including impulse oscillometry. He
has written numerous book
chapters and journal articles and
has edited multiple chapters for
eMedicine, the online textbook of
pediatrics. He was trained at the
Great Ormond Street Hospital for
Children, London, UK, and at the
Rainbow Babies and Children?s
Hospital, Case Western Reserve
University, Cleveland.
Sharma-Girish.qxp 19/12/05 9:18 am Page 64
Please see complete Prescribing Information on adjacent page
REFERENCES: 1. Konstan M et al. ULTRASE MT12® in the treatment of exocrine pancreatic insufficiency in cystic fibrosis:
safety and efficacy, Abstract #428, The 18th Annual North American Cystic Fibrosis Conference, St. Louis, MO, Oct. 14-17,
2004. 2. Data on file, Axcan PharmaTM, 2004
ULTRASE® and ULTRASE® MT are manufactured by Eurand International, Milan, Italy using its DIFFUCAPS® or EURAND MINITABS® technology for Axcan Scandipharm Inc.
® Registered trademarks and ? trademarks are used under license by Axcan Scandipharm Inc.
? Comprehensive patient support
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g87g03g33g55g52g59g48g51g03g56g5cg50g53g57g52g50g44g57g4cg46g03g55g48g4fg4cg48g492
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Axcan_ad.qxp 19/12/05 10:39 am Page 5
ULTRASE®
(?ul-tras)
(pancrelipase) Capsules
Enteric-Coated Microspheres
Prescribing Information
DESCRIPTION:
ULTRASE® (pancrelipase) Capsules are orally administered and contain 250 mg of enteric-coated
microspheres of porcine pancreatic enzyme concentrate, predominantly pancreatic lipase, amylase,
and protease.
Each ULTRASE® Capsule contains:
Lipase..................................................................................... 4,500 U.S.P. Units
Amylase................................................................................. 20,000 U.S.P. Units
Protease................................................................................. 25,000 U.S.P. Units
Inactive ingredients: povidone, talc, sugar, methacrylic acid copolymer (Type C), triethyl citrate, simethi-
cone emulsion.
CLINICAL PHARMACOLOGY:
ULTRASE® (pancrelipase) Capsules are designed to prevent inactivation by gastric acid thereby resulting
in the delivery of high levels of biologically active enzymes into the duodenum. The enzymes catalyze
the hydrolysis of fats into glycerol and fatty acids, starch into dextrins and sugars, and protein into
proteoses and derived substances.
INDICATIONS AND USAGE:
ULTRASE® (pancrelipase) Capsules are indicated for patients with partial or complete exocrine pancre-
atic insufficiency caused by:
Cystic fibrosis (CF)
Chronic pancreatitis due to alcohol use or other causes
Surgery (pancreatico-duodenectomy or Whipple?s procedure, with or without Wirsung duct
injection,total pancreatectomy)
Obstruction (pancreatic and biliary duct lithiasis, pancreatic and duodenal neoplasms,
ductal stenosis)
Other pancreatic disease (hereditary, post traumatic and allograft pancreatitis, hemochromatosis,
Shwachman?s Syndrome, lipomatosis, hyperparathyroidism)
Poor mixing (Billroth II gastrectomy, other types of gastric bypass surgery, gastrinoma)
Pancrelipase capsules are effective in controlling steatorrhea.1-9
CONTRAINDICATIONS:
Pancrelipase capsules are contraindicated in patients known to be hypersensitive to pork protein.
Pancrelipase capsules are contraindicated in patients with acute pancreatitis or with acute exacerba-
tions of chronic pancreatic diseases.
WARNINGS:
Should hypersensitivity occur, discontinue medication and treat symptomatically.
PRECAUTIONS:
General
TO PROTECT ENTERIC COATING, MICROSPHERES MUST NOT BE CRUSHED OR CHEWED. Where swal-
lowing of capsules is difficult, they may be opened and the microspheres added to a small quantity of
a soft food (e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed immediately.
Contact of the microsphere with foods having a pH greater than 5.5 can dissolve the protective enteric
shell.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Methacrylic
acid, a minor component of the methacrylic acid copolymer enteric-coating contained in ULTRASE®
(pancrelipase) Capsules, has been reported to act as a teratogen in rat embryo cultures. However, the
copolymer enteric-coating of ULTRASE® (pancrelipase) Capsules was not mutagenic by the Ames test,
and it did not produce chromosome damage in a test for unscheduled DNA synthesis in rat hepatocytes.
Pregnancy: Category C.
Animal reproduction studies have not been conducted with ULTRASE® (pancrelipase) Capsules. It is not
known whether ULTRASE® (pancrelipase) Capsules can cause fetal harm when administered to a preg-
nant woman or can affect reproduction capacity. ULTRASE® (pancrelipase) Capsules should be given to
a pregnant woman only if the potential benefit outweighs the potential risk to the fetus.
Nursing Mothers
It is not known whether ULTRASE® (pancrelipase) is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when ULTRASE® (pancrelipase) Capsules are
administered to a nursing mother.
ADVERSE REACTIONS:
The most frequently reported adverse reactions to products containing pancrelipase are gastrointestinal
in nature. Less frequently, allergic-type reactions have also been observed. Extremely high doses of
exogenous pancreatic enzymes have been associated with hyperuricosuria and hyperuricemia when the
preparations given were pancrelipase in powdered or capsule form, or pancreatin in tablet form.
Colonic strictures have been reported in cystic fibrosis patients treated with both high- and lower-
strength enzyme supplements.10 A causal relationship has not been established. The possibility of
bowel stricture should be considered if symptoms suggestive of gastrointestinal obstruction occur.
Since impaired fluid secretion may be a factor in the development of intestinal obstruction, care should
be taken to maintain adequate hydration, particularly in warm weather.11
?Fibrosing colonopathy? is a term used to describe a condition seen in patients with CF who have taken
high amounts of pancreatic enzyme supplements (>6,000 lipase U/kg/meal). At its most advanced, this
condition leads to colonic strictures.
1. In whom should one consider the diagnosis of fibrosing colonopathy?
a. Patients with cystic fibrosis who have evidence of partial or complete obstruction, bloody diarrhea or
chylous ascites.
b. Patients who have two of the following three symptoms:
abdominal pain
ongoing diarrhea
poor weight gain
ESPECIALLY if they have:
taken >6,000 lipase U/kg/meal
age less than twelve years
history of meconium ileus
prior intestinal surgery
history of recurrent DIOS
?inflammatory bowel disease?12
DOSAGE AND ADMINISTRATION:
The enzymatic activity of ULTRASE® (pancrelipase) Capsules is expressed in U.S.P. units.
The smallest effective dose should be used. Dosage should be adjusted according to
the severity of the exocrine pancreatic insufficiency. Begin therapy with one or two capsules with meals
or snacks and adjust dosage according to symptoms. The number of capsules or capsule strength given
with meals and/or snacks should be estimated by assessing which dose minimizes steatorrhea and
maintains good nutritional status. Dosages should be adjusted according to the response of the patient.
Where swallowing of capsules is difficult, they may be opened and the microspheres added to a small
quantity of a soft food (e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed
immediately. It is recommended that the total dose of pancrelipase being ingested for a meal or snack
be dispersed equally (with fluids) before, during, and after the meal or snack.
SUGGESTIONS FOR THE USE OF PANCREATIC ENZYMES IN CYSTIC FIBROSIS12
1. Patients should be receiving optimal diet for age and clinical status, recognizing that those with
failure to thrive or malnutrition require additional calories and other nutrients for catch-up growth.
2. Nutrition assessment should be a part of routine clinical evaluations.
3. Initial dosing of pancreatic enzyme supplements should begin with 500 lipase U/kg/meal using
enteric-coated microsphere products.
4. Patients should be reassessed 2-4 weeks after initiation of therapy. The following items should
be assessed:
Clinical status, e.g., abdominal symptoms and exam;
Nutritional intake and growth (height, weight, head circumference);
Character of stools - greasy, oily (for information, not for decision making);
Quantitative 72-hour fecal fat when indicated but not less than annually (perform on a normal
diet for age);
Fat soluble vitamin measures.
5. Corollaries to dosing suggestions:
a. Dose may be altered in a stepwise fashion according to the response of the patient (see 4. above).
b. Dose approaching 2,000 lipase U/kg/meal would indicate the need for further investigation (see
below). Patients presently on higher doses should be reevaluated; either immediately decrease the dose
or titrate down to a lower dose range at, or below, 2,000 lipase U/kg/meal. Doses >6,000 lipase
U/kg/meal have been associated with colonic strictures.
c. Pancreatic supplements mixed with applesauce or other acidic food substances should be
administered immediately, not stored.
d. Enteric-coated microspheres should not be crushed.
e. Enzyme doses (as lipase U/kg/meal) tend to decrease with advancing age.
f. Patients should accept only product brands prescribed by their physician.
g. Adjustment of dosage is the responsibility of the physician. Patients should be advised not to
adjust doses without consulting their physician. Changes in product or dosage may require an
adjustment period.
h. Complaints transmitted by phone should be investigated thoroughly before dose is adjusted. If
indicated, this investigation should include 72-hour fecal fat testing.
i. Pancreatic supplements should be stored in a cool, dry place and checked regularly for expiration date.
HOW SUPPLIED:
ULTRASE® (pancrelipase) Capsules
Gelatin capsules (opaque white and opaque white), imprinted ?ULTRASE?. Bottles of 100 (NDC 58914-045-10).
Store at controlled room temperature, between 15°C and 25°C (59°F and 77°F), in a dry place. Do
not refrigerate.
REFERENCES:
1. Delchier JC, Vidon N, et al. Fate of orally ingested enzymes in pancreatic insuffciency: comparison
of two pancreatic enzyme preparations. Aliment Pharmacol Therap. 1991;5:365-378.
2. Duhamel JP, Vidailhet M, et al. Étude multicentrique comparative d?une nouvelle présentation de
pancréatine en microgranules gastrorésistants dans I?insuffisance pancréatique exocrine de la
mucoviscidose chez l?enfant. Ann Pediatr. 1988;35:69-74.
3. DuttaSK, Tilley DK.The pH-sensitive enteric-coatedpancreaticenzymepreparations: an evaluation of
therapeutic efficacy in adult patients with pancreatic insufficiency. J Clin Gastroenterol. 1983;5:51-54.
4. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive
enteric-coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the
treatment of exocrine pancreatic insufficiency. Gastroenterol. 1983;84:476-482.
5. Gouerou H, Dain MP, et al. Alipase versus nonenteric-coated enzymes in pancreatic insufficiency.
Int J Pancreatol. 1989;5:45-50.
6. Mischler EH, Parrell S, et al. Comparison of effectiveness of pancreatic enzyme preparations in
cystic fibrosis. Am J Dis Child. 1982;136:1060-1063.
7. Salen G, Prakash A. Evaluation of enteric-coated microspheres for enzyme replacement
therapy in adults with pancreatic insufficiency. Cur Ther Res. 1979;25:650-656.
8. Schneider MU, Knoll-Ruzicka ML, et al. Pancreatic enzyme replacement therapy: comparative effects
of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme
preparations on steatorrhea in chronic pancreatitis. Hepatogastroenterol. 1985;32:97-102.
9. Halgreen H, Thorsgaard Pedersen N, Worning H. Symptomatic effect of pancreatic enzyme therapy
in patients with chronic pancreatitis. Scand J Gastroenterol. 1986;21:104-108.
10. Smyth RL, van Velzen D, et al. Strictures of ascending colon in cystic fibrosis and high-strength
pancreatic enzymes. The Lancet. 1994;343:85-86.
11. Lands L, Zinman R, et al. Pancreatic function testing in meconium disease in CF: two case reports.
J Ped Gastroenterol and Nut. 1988;7:276-279.
12. Cystic Fibrosis Foundation Conference on Pancreatic Enzyme Supplementation in the Context of
Fibrosing Colonopathy; Washington, D.C., March 23-24, 1995.
Rx only
REV. June 2005
Marketed as ULTRASE® by:
AXCAN SCANDIPHARM INC.
22 Inverness Center Parkway
Birmingham, AL 35242 USA
www.axcan.com
ULTRASE® is manufactured by Eurand International, Milan, Italy using its DIFFUCAPS® technology for
Axcan Scandipharm Inc., 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA. ULTRASE®,
Axcan Pharma? and the Axcan Pharma? logo are registered trademarks or trademarks used under
license by Axcan Scandipharm Inc.
©2005 Axcan Scandipharm Inc.
Printed in USA
2306020-01
ULTRASE® MT
(?ul-tras)
(pancrelipase) Capsules
Enteric-Coated Minitablets
Prescribing Information
DESCRIPTION:
ULTRASE® MT (pancrelipase) Capsules are orally administered capsules containing enteric-coated
minitablets of porcine pancreatic enzyme concentrate, predominantly pancreatic lipase, amylase, and
protease.
Each ULTRASE® MT12 Capsule is orally administered and contains 223 mg of enteric-coated minitablets
of porcine pancreatic concentrate containing:
Lipase.................................................................................................... 12,000 U.S.P. Units
Amylase................................................................................................. 39,000 U.S.P. Units
Protease........................................................................................... ..... 39,000 U.S.P. Units
Each ULTRASE® MT18 Capsule is orally administered and contains 333 mg of enteric-coated minitablets
of porcine pancreatic concentrate containing:
Lipase.................................................................................................... 18,000 U.S.P. Units
Amylase................................................................................................. 58,500 U.S.P. Units
Protease................................................................................................. 58,500 U.S.P. Units
Each ULTRASE® MT20 Capsule is orally administered and contains 371 mg of enteric-coated minitablets
of porcine pancreatic concentrate containing:
Lipase.................................................................................................... 20,000 U.S.P. Units
Amylase................................................................................................. 65,000 U.S.P. Units
Protease................................................................................................. 65,000 U.S.P. Units
Inactive ingredients: gelatin, hydrogenated castor oil, silicon dioxide, magnesium stearate, croscar-
mellose sodium, microcrystalline cellulose, hydroxypropyl methylcellulose phthalate (HP 55) (as dry
substance), talc, triethyl citrate, iron oxides and titanium dioxide.
CLINICAL PHARMACOLOGY:
ULTRASE® MT (pancrelipase) Capsules are designed to prevent inactivation by gastric acid thereby
resulting in the delivery of high levels of biologically active enzymes into the duodenum. The enzymes
catalyze the hydrolysis of fats into glycerol and fatty acids, starch into dextrins and sugars, and protein
into proteoses and derived substances.
INDICATIONS AND USAGE:
ULTRASE® MT (pancrelipase) Capsules are indicated for patients with partial or complete exocrine
pancreatic insufficiency caused by:
Cystic fibrosis (CF)
Chronic pancreatitis due to alcohol use or other causes
Surgery (pancreatico-duodenectomy or Whipple?s procedure, with or without Wirsung duct
injection, total pancreatectomy)
Obstruction (pancreatic and biliary duct lithiasis, pancreatic and duodenal neoplasms,
ductal stenosis)
Otherpancreatic disease (hereditary, post traumatic and allograft pancreatitis, hemochromatosis,
Shwachman?s Syndrome, lipomatosis, hyperparathyroidism)
Poor mixing (Billroth II gastrectomy, other types of gastric bypass surgery, gastrinoma)
Pancrelipase capsules are effective in controlling steatorrhea.1-9
CONTRAINDICATIONS:
Pancrelipase capsules are contraindicated in patients known to be hypersensitive to pork protein.
Pancrelipase capsules are contraindicated in patients with acute pancreatitis or with acute exacerba-
tions of chronic pancreatic diseases.
WARNINGS:
Should hypersensitivity occur, discontinue medication and treat symptomatically.
PRECAUTIONS:
General
TO PROTECT ENTERIC COATING, MINITABLETS MUST NOT BE CRUSHED OR CHEWED. Where swallowing
of capsules is difficult, they may be opened and the minitablets added to a small quantity of a soft food
(e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed immediately. Contact of
the minitablet with foods having a pH greater than 5.5 can dissolve the protective enteric shell.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Pregnancy: Category C.
Animal reproduction studies have not been conducted with ULTRASE® MT (pancrelipase) Capsules. It is
not known whether ULTRASE® MT (pancrelipase) Capsules can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. ULTRASE® MT (pancrelipase) Capsules should be
given to a pregnant woman only if the potential benefit outweighs the potential risk to the fetus.
Nursing Mothers
It is not known whether ULTRASE® MT (pancrelipase) is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when ULTRASE® MT (pancrelipase) Capsules
are administered to a nursing mother.
ADVERSE REACTIONS:
The most frequently reported adverse reactions to products containing pancrelipase are gastrointestinal
in nature. Less frequently, allergic-type reactions have also been observed. Extremely high doses of
exogenous pancreatic enzymes have been associated with hyperuricosuria and hyperuricemia when the
preparations given were pancrelipase in powdered or capsule form, or pancreatin in tablet form.
In two clinical studies with ULTRASE® MT in 193 patients with cystic fibrosis, the adverse events
described were all gastrointestinal in nature and may actually represent symptoms of the underlying
disease, such as abdominal pain/cramps (5.7%), diarrhea (3.6%), and greasy stools and flatulence
(1.5% each). In a postmarketing trial with another enteric-coated formulation, 160 adverse events
occurred in the 15,711 patients (0.97%) evaluated.10 The most frequent events reported were diarrhea,
skin reaction, and abdominal discomfort (0.2% each).
Colonic strictures have been reported in cystic fibrosis patients treated with both high- and lower-
strength enzyme supplements.11 A causal relationship has not been established. The possibility of bowel
stricture should be considered if symptoms suggestive of gastrointestinal obstruction occur. Since
impaired fluid secretion may be a factor in the development of intestinal obstruction, care should be
taken to maintain adequate hydration, particularly in warm weather.12
?Fibrosing colonopathy? is a term used to describe a condition seen in patients with CF who have taken
high amounts of pancreatic enzyme supplements (>6,000 lipase U/kg/meal). At its most advanced, this
condition leads to colonic strictures.
1. In whom should one consider the diagnosis of fibrosing colonopathy?
a. Patients with cystic fibrosis who have evidence of partial or complete obstruction, bloody
diarrhea or chylous ascites.
b. Patients who have two of the following three symptoms:
abdominal pain
ongoing diarrhea
poor weight gain
ESPECIALLY if they have:
taken >6,000 lipase U/kg/meal
age less than twelve years
history of meconium ileus
prior intestinal surgery
history of recurrent DIOS
?inflammatory bowel disease?13
DOSAGE AND ADMINISTRATION:
The enzymatic activity of ULTRASE® MT (pancrelipase) Capsules is expressed in U.S.P. units. The small-
est effective dose should be used. Dosage should be adjusted according to the severity of the exocrine
pancreatic insufficiency. Begin therapy with one or two capsules with meals or snacks and adjust
dosage according to symptoms. The number of capsules or capsule strength given with meals and/or
snacks should be estimated by assessing which dose minimizes steatorrhea and maintains good nutri-
tional status. Dosages should be adjusted according to the response of the patient. Where swallowing
of capsules is difficult, they may be opened and the minitablets added to a small quantity of a soft food
(e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed immediately. It is recom-
mended that the total dose of pancrelipase being ingested for a meal or snack be dispersed equally
(with fluids) before, during, and after the meal or snack.
SUGGESTIONS FOR THE USE OF PANCREATIC ENZYMES IN CYSTIC FIBROSIS13
1. Patients should be receiving optimal diet for age and clinical status, recognizing that those with
failure to thrive or malnutrition require additional calories and other nutrients for catch-up growth.
2. Nutrition assessment should be a part of routine clinical evaluations.
3. Initial dosing of pancreatic enzyme supplements should begin with 500 lipase U/kg/meal using
enteric-coated minitablet products.
4. Patients should be reassessed 2-4 weeks after initiation of therapy. The following items
should be assessed:
Clinical status, e.g., abdominal symptoms and exam;
Nutritional intake and growth (height, weight, head circumference);
Character of stools - greasy, oily (for information, not for decision making);
Quantitative 72-hour fecal fat when indicated but not less than annually (perform
on a normal diet for age);
Fat soluble vitamin measures.
5. Corollaries to dosing suggestions:
a. Dose may be altered in a stepwise fashion according to the response of the patient (see 4. above).
b. Dose approaching 2,000 lipase U/kg/meal would indicate the need for further investigation
(see below). Patients presently on higher doses should be reevaluated; either immediately
decrease the dose or titrate down to a lower dose range at, or below, 2,000 lipase U/kg/
meal. Doses >6,000 lipase U/kg/meal have been associated with colonic strictures.
c. Pancreatic supplements mixed with applesauce or other acidic food substances should
be administered immediately, not stored.
d. Enteric-coated minitablets should not be crushed.
e. Enzyme doses (as lipase U/kg/meal) tend to decrease with advancing age.
f. Patients should accept only product brands prescribed by their physician.
g. Adjustment of dosage is the responsibility of the physician. Patients should be advised not to
adjust doses without consulting their physician. Changes in product or dosage may require an
adjustment period.
h. Complaints transmitted by phone should be investigated thoroughly before dose is adjusted. If
indicated, this investigation should include 72-hour fecal fat testing.
i. Pancreatic supplements should be stored in a cool, dry place and checked regularly
for expiration date.
HOW SUPPLIED:
ULTRASE® MT12 (pancrelipase) Capsules
Gelatin capsules (white and yellow), imprinted ?ULTRASE MT12?. Bottles of 100 (NDC 58914-002-10).
ULTRASE® MT18 (pancrelipase) Capsules
Gelatin capsules (gray and white), imprinted ?ULTRASE MT18?. Bottles of 100 (NDC 58914-018-10).
ULTRASE® MT20 (pancrelipase) Capsules
Gelatin capsules (light gray and yellow), imprinted ?ULTRASE MT20?. Bottles of 100
(NDC 58914-004-10), and bottles of 500 (NDC 58914-004-50).
Store at controlled room temperature, between 15°C and 25°C (59°F and 77°F), in a dry place. Do
not refrigerate.
REFERENCES:
1. Delchier JC, Vidon N, et al. Fate of orally ingested enzymes in pancreatic insufficiency:
comparison of two pancreatic enzyme preparations. Aliment Pharmacol Therap. 1991;5:365-378.
2. Duhamel JP, Vidailhet M, et al. Étude multicentrique comparative d?une nouvelle présentation
de pancréatine en microgranules gastrorésistants dans I?insuffisance pancréatique exocrine
de la mucoviscidose chez l?enfant. Ann Pediatr. 1988;35:69-74.
3. Dutta SK, Tilley DK. The pH-sensitive enteric-coated pancreatic enzyme preparations: an evaluation
of therapeutic efficacy in adult patients with pancreatic insufficiency. J Clin Gastroenterol. 1983;5:51-54.
4. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive
enteric-coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the
treatment of exocrine pancreatic insufficiency. Gastroenterol. 1983;84:476-482.
5. Gouerou H, Dain MP, et al. Alipase versus nonenteric-coated enzymes in pancreatic
insufficiency. Int J Pancreatol. 1989;5:45-50.
6. Mischler EH, Parrell S, et al. Comparison of effectiveness of pancreatic enzyme preparations
in cystic fibrosis. Am J Dis Child. 1982;136:1060-1063.
7. Salen G, Prakash A. Evaluation of enteric-coated microspheres for enzyme replacement
therapy in adults with pancreatic insufficiency. Cur Ther Res. 1979;25:650-656.
8. Schneider MU, Knoll-Ruzicka ML, et al. Pancreatic enzyme replacement therapy: comparativeeffects
of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme prepa-
rations on steatorrhea in chronic pancreatitis. Hepatogastroenterol. 1985;32:97-102.
9. Halgreen H, Thorsgaard Pedersen N, Worning H. Symptomatic effect of pancreatic enzyme
therapy in patients with chronic pancreatitis. Scand J Gastroenterol. 1986;21:104-108.
10. Gretzmacher I, Rüther HG. Maldigestion. Therapiewoche. 1983;33:6776-6782.
11. Smyth RL, van Velzen D, et al. Strictures of ascending colon in cystic fibrosis and high-strength
pancreatic enzymes. The Lancet. 1994;343:85-86.
12. Lands L, Zinman R, et al. Pancreatic function testing in meconium disease in CF: two case
reports. J Ped Gastroenterol and Nut. 1988;7:276-279.
13. Cystic Fibrosis Foundation Conference on Pancreatic Enzyme Supplementation in the Context of
Fibrosing Colonopathy; Washington, D.C., March 23-24, 1995.
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The Pathophysiology, Diagnosis, and Investigation of Cystic Fibrosis
B USINESS BRIEFING: US RESPIRATORY CARE 2006
67
present with digestive symptoms and/or failure to
thrive early in life. However, onset of PI varies and may
occur in patients older than six months.
Some patients never develop PI. Patients with PI
typically present with poor weight gain in association
with frequent stools that are malodorous, greasy, and
associated with flatulence and colicky pain after feeding.
The combination of increased energy intake demand at
baseline, the added energy intake demand of chronic
disease, the difficulty of sustaining energy uptake
because of malabsorption, and anorexia associated with
on-going lung inflammation leads to poor weight gain.
PI predisposes patients to poor absorption of the fat-
soluble vitamins A, D, E, and K. Symptomatic deficiency
of any of these vitamins can occur before diagnosis or as
a later complication of the disease.
Pathophysiology of Liver Disease
Absence of functional CFTR in epithelial cells lining
the biliary ductules leads to reduced secretion of
chloride and reduction in passive transport of water and
chloride, resulting in increased viscosity of bile. The
biliary ductules may be plugged with secretions.
Secondary involvement of the liver may also occur
because of involvement of other organs; for example,
malnutrition may be associated with hepatic steatosis,
and right heart failure caused by chronic hypoxia may
result in passive congestion of the liver. Gallstones are
more prevalent in patients with CF than in age-matched
control subjects.As many as 15% of young adults with
CF have gallstones, irrespective of the status of
pancreatic function.Abnormal mucin in the gallbladder
and malabsorption of bile acids in a patient with PI
result in a higher frequency of gallstones.
Clinical Features
Gastrointestinal Tract Manifestations
At birth, infants may present with intestinal obstruction
and a variety of surgical findings,such as meconium ileus
(7?10% of patients with CF), volvulus, intestinal atresia,
perforation, and meconium peritonitis. Less commonly,
passage of meconium may be delayed (>24?48h after
birth) or cholestatic jaundice may be prolonged.
Infants and children may present with failure to thrive
(despite an adequate appetite), flatulence or foul-
smelling flatus, recurrent abdominal pain, and
abdominal distention. Steatorrhea is characterized by
frequent, poorly formed, large, bulky, foul-smelling,
greasy stools that float in water. Cloth diapers, if used,
are difficult to clean. Intussusception (ileocecal) or
rectal prolapse can constitute the initial presentation.
Patients with PI may develop fat-soluble vitamin
deficiency and malabsorption of fats, proteins, and
carbohydrates; however, malabsorption of carbo-
hydrates is not as severe as that of fats and proteins.
Alternatively, some patients have anorexia without
obvious steatorrhea. Many infants have symptoms of
gastroesophageal reflux.Abdominal distention, hepato-
splenomegaly (fatty liver and portal hypertension),
rectal prolapse, dry skin (vitamin A deficiency), and
chielosis (vitamin B complex deficiency) may be seen
on examination.
Respiratory Tract Manifestations
Patients present with a chronic or recurrent cough that
can be dry and hacking at the beginning and can
produce mucoid (early) and purulent (later) sputum.
Prolonged symptoms of bronchiolitis occur in infants.
Paroxysmal cough followed by vomiting may occur.
Recurrent wheezing or pneumonia, atypical asthma,
pneumothorax, hemoptysis, and digital clubbing are all
complications and may constitute the initial mani-
festation. Dyspnea on exertion, history of chest pain,
recurrent sinusitis, nasal polyps, and hemoptysis may
occur. Tachypnea, respiratory distress with retractions,
wheeze or crackles, cough (dry or productive of
mucoid or purulent sputum), increased anteroposterior
diameter of chest, and hyperresonant chest on
percussion may be noted. Crackles are heard acutely in
associated pneumonitis or bronchitis and chronically
with bronchiectasis.
Urogenital Tract Manifestations
Males with CF are frequently sterile because of the
absence of the vas deferens. Undescended testicles or
hydrocele may exist. Fertility is maintained, although
possibly decreased, in females. Secondary sexual
development is often delayed. Amenorrhea may occur
in patients with severe nutritional or pulmonary
involvement. In patients with advanced disease, scoliosis
and kyphoscoliosis due to osteopenia secondary to
vitamin D deficiency may develop.
Diagnosis
The diagnosis of CF is based on typical pulmonary
and/or gastrointestinal tract manifestations, family
history, and positive results on sweat test.
Sweat Test
Several methods are used to conduct a sweat test.
Performed properly, the quantitative pilocarpine
iontophoresis test (QPIT) to collect sweat and perform a
chemical analysis of its chloride content is currently
considered to be the only adequately sensitive and specific
type of sweat test. For reliable results, at least 50mg or,
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B USINESS BRIEFING: US RESPIRATORY CARE 2006
Cystic Fibrosis
preferably, 100mg of sweat should be collected.The sweat
chloride reference value is less than 40 milliequivalent
(meq)/litre, and a value of more than 60meq/litre of
chloride in the sweat is consistent with a diagnosis of CF.
Values of 40?60meq/litre are considered borderline, and
the test must be repeated because these values have been
found to be consistent with the diagnosis in some patients
with typical features.A repeat sweat test is always needed
to confirm positive results. A sweat test with negative
results should be repeated if clinical features suggestive of
CF are present. For some patients with typical symptoms,
sweat test results are consistently negative and genotyping
for CF mutations can be helpful to confirm the diagnosis.
The sweat test can be negative in patients with untreated
adrenal insufficiency, glycogen storage disease, type I
fucosidosis, hypothyroidism, vasopressin-resistant diabetes
insipidus, ectodermal dysplasia, severe malnutrition,
mucopolysaccharidosis, panhypopituitarism, familial
cholestasis, familial hypoparathyroidism, atopic dermatitis,
and iatrogenic causes (i.e. infusion of prostaglandin E1,
improper technique).
Investigations
Chest X-ray
Initial changes are hyperinflation and peribronchial
thickening. Progressive airtrapping with bronchiectasis
may be apparent in the upper lobes. With advancing
pulmonary disease, pulmonary nodules resulting from
abscesses, infiltrates with or without lobar atelectasis,
marked hyperinflation with flattened domes of the
diaphragm, thoracic kyphosis, and bowing of the
sternum develop. Pulmonary artery dilatation and right
ventricular hypertrophy associated with cor pulmonale
is usually masked by marked hyperinflation.
Sinus X-ray
Pan-opacification of the sinuses is present in almost all
patients with CF, and its presence is strongly suggestive of
the diagnosis. Conversely, absence of pan-opacification
strongly suggests that CF is not present. Computed
tomography (CT) of the chest,among other changes seen
on the chest X-ray, can show bronchiectatic changes.
CF Genotyping
More than 1,000 mutations of CFTR have been
identified. Most of the current commercially available
probes identify 87 of the most common known
mutations.These probes identify two mutations in more
than 90% of all white patients with CF and in 97% of
the Ashkenazi Jewish population.The detection rate is
lower in African-American, Hispanic, and Asian
populations; therefore, failure to find two abnormal
genes does not exclude the disease. A finding of two
CFTR mutations in association with clinical symptoms
is diagnostic, but negative results on genotype analysis
do not exclude the diagnosis. Some laboratories have
recently developed full CF gene sequencing that can
identify up to 99% of the known abnormal mutations.
Semen Analysis
Obstructive azoospermia, in the absence of any other
obvious cause (e.g. vasectomy), provides additional
corroborative evidence for the diagnosis of CF.
Nasal Potential Difference Measurement
Potential difference (PD) measured from nasal mucosa
and the reading obtained by a reference electrode
inserted into the forearm correlate with the movement
of sodium across cell membranes, which is a physio-
logical function rendered abnormal by a CFTR
mutation. A normal mean value standard error (SE) is
0.9?24.7mV; an abnormal value is 1.8?53mV. When
measurements are repeated after mucosal perfusion with
amiloride to block an epithelial sodium channel, the
drop in PD is greater in patients with CF (73%) than in
control subjects (53%). Normally, subsequent perfusion
with chloride-free solution and isoproterenol produces
a sharp increase in the PD, but has little effect when
CFTR function is abnormal. Due to the lack of
commercially available equipment and the practical
difficulties with nasal PD measurement, this test is
performed in only a few research centers to diagnose CF
in patients in whom other methods are impossible.
Pulmonary Function Testing
A typical finding when performing pulmonary function
testing is an obstructive defect with airtrapping and
hyperinflation. In advanced pulmonary disease,
oxyhemoglobin desaturation may occur because of a
ventilation?perfusion mismatch. In the early stages,
forced expiratory volume in one second (FEV1) may be
normal and forced expiratory flow (FEF) is reduced after
25?75% of vital capacity has been expelled (FEF25?75),
suggesting small-airway involvement. As the disease
progresses, FEV1 is also reduced. The associated air
trapping results in an elevated ratio of residual volume
(RV) to total lung capacity (TLC).With hyperinflation,
TLC is also increased. In patients with advanced disease,
extensive lung changes with fibrosis are reflected as
restrictive changes characterized by declining TLC and
vital capacity. Standard spirometry may not be reliable
until patients are aged five to six years; however, some
younger patients can be taught to do reproducible
maneuvers. Partial flow volume curves may show
abnormalities in addition to an elevated airway resistance
and hyperinflation. Recently, other methods of lung
function measurements, such as impulse oscillometry to
Sharma-Girish.qxp 19/12/05 9:20 am Page 68
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70
B USINESS BRIEFING: US RESPIRATORY CARE 2006
Cystic Fibrosis
measure airway resistance, are being investigated. Due to
the fact that this technique does not require voluntary
forced exhalation, as is the case in spirometry, and
measurement can be performed during tidal breathing,
the maneuver is possible in young patients older than
three years in whom spirometry may not be possible.
Sputum Microbiology
The most common bacterial pathogens in the sputum
of patients with CF are Haemophilus influenzae,
Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia
cepacia, Escherichia coli, and Klebsiella pneumoniae.
Findings of P. aeruginosa, especially the mucoid form,
support the diagnosis of CF in children.
Bronchoalveolar Lavage
Airway inflammation is the hallmark of CF lung disease.
Studies suggest airway inflammation,even in the absence
of infection. Bronchoalveolar lavage fluid usually shows
a high percentage of neutrophils, and recovery of
P. aeruginosa from bronchoalveolar lavage fluid supports
the diagnosis of CF in a clinically atypical case.
Treatment
The primary goals of CF treatment include maintaining
lung function as near to normal as possible by controlling
respiratory infection, clearing airways of mucus, admin-
istering nutritional therapy (i.e.enzyme,multivitamin,and
mineral supplements) to maintain adequate growth, and
managing complications. Mild acute pulmonary
exacerbations of CF can be treated at home through
increased frequency of airway clearance; inhaled
bronchodilator treatment, chest physical therapy, and
postural drainage;increased dose of dornase alpha;and the
use of oral antibiotics, e.g. oral fluoroquinolones.
Pancreatic Enzyme and
Vitamin Supplements
Current pancreatic enzyme preparations are derived
from porcine extracts and contain various proportions of
lipase, amylase, and protease. Most of the preparations are
available in multiple strengths. A particular dose is
prescribed, based on clinical symptoms, age, and weight
of the patient, and modified according to clinical
response. Usually, the pancreatic enzyme dose should not
exceed 2,000 units of lipase per kg of weight per meal.
The novel preparation TheraCLEC-Total (TCT), a
highly purified microbially derived enzyme preparation,
is being investigated in clinical trials.
Special preparations containing fat-soluble vitamins,
such as ADEK and ABDEC, are available in various
forms and constitute an important part of treatment.
Airway Clearance
A combination of bronchodilator treatment in inhaled
form, chest physical therapy (either by hand or using
instruments such as a flutter device), therapy vest,
suction cup, and postural drainage constitute airway
clearance. These are usually combined with other
therapeutic agents, such as nebulized dornase alpha.
Mucolytic Agents
Large amounts of neutrophil-derived DNA released
from the dead neutrophils increase sputum viscosity.
Mucolytics, such as dornase alpha (an enzyme that
hydrolyses the DNA), are used in patients with CF to
improve airway clearance.Dornase alpha?recombinant
human (rh)DNase?cleaves and depolymerizes
extracellular DNA and separates DNA from proteins.
This allows endogenous proteolytic enzymes to break
down the proteins,decreasing viscoelasticity and surface
tension of purulent sputum.The usual dose is 2.5mg via
nebulizer once or twice daily.
Antibiotic Therapy
Antibiotic treatment may vary from a short course of
one antibiotic agent to a continuous course with
multiple antibiotics administered via various routes,
including orally, intravenously (IV), or through
inhalation.As patients with CF have a larger lean body
mass, they often have a higher clearance rate for many
antibiotics. Achieving effective levels in respiratory
secretions is difficult; higher doses of antibiotics and
monitoring of aminoglycoside levels are required.
Aerosolized antibiotics may reduce symptoms by
reducing the organism density in the airways.They may
also prevent infection or delay chronic colonization, treat
acute infection,and treat bacterial colonization in patients
following transplantation to prevent infection in the
transplanted lungs. Of all the agents used in the
aerosolized form (e.g. gentamicin, colistin, and
tobramycin), preservative-free high-dose tobramycin
especially formulated for inhalation (TOBI) has been
used in two large controlled studies and has been reported
to be safe and effective in patients older than six months.
The usual dose is 300mg twice-daily, which is given
during alternate months. Currently, clinical trials using a
powder form of tobramycin and colimycin are under way.
These preparations will use novel drug delivery devices.
Cephalosporins are effective against staphylococci and
H. influenzae.A small subset of third-generation
cephalosporins is effective against P. aeruginosa.
Generally speaking, moving from first-generation to
third-generation cephalosporins provides more gram-
negative and less gram-positive coverage.
Sharma-Girish.qxp 19/12/05 9:20 am Page 70
Fluoroquinolones are effective against most gram-
positive and -negative organisms.They are the only class
of oral antibiotics effective against P. aeruginosa.The most
commonly used medication in this class is ciprofloxacin.
During an acute pulmonary exacerbation of CF, a two-
week course of either oral antibiotics (e.g. fluoro-
quinolones or other agents, depending on respiratory
cultures) or intravenous antibiotics, usually a combination
of aminoglycoside and semi-synthetic penicillin, is
administered. In patients with colonization with P.
aeruginosa, azithromycin administered orally three days a
week on a long-term basis has, in recent years, been
shown to improve lung function and nutritional status
and reduce acute pulmonary exacerbations.The dose of
azithromycin is 250mg three days a week for patients of
less than 40kg body weight and 500mg three days a week
for patients of more than 40kg body weight.
Diet and Activity
In general, a normal diet with additional energy and
unrestricted fat intake is recommended.A high-energy
and high-fat diet, in addition to vitamin (especially fat-
soluble) and mineral supplementation, is recommended
to compensate for malabsorption and the increased
energy demand of chronic inflammation. In children,
because of a variety of physical activities and eating
habits, base assessment and modification of energy
requirements depend on growth and weight gain.
Special consideration is given to female patients with a
potential for delayed puberty because of malnutrition,
patients with diabetes mellitus and patients with liver
disease. Nutritional supplements in the form of either
high-energy oral preparations or enteral feeds (e.g.
elemental formulas and high-fat mixtures) via
nasogastric tube or gastrostomy may be indicated in
some patients. Regular exercise increases physical fitness
in patients with CF. Upper body exercises, such as canoe
paddling, may increase respiratory muscle endurance.
General Medical and Surgical Care
As a result of the complex and multisystemic
involvement of CF and the need for care by specialists,
treatment and follow-up care at specialty centers with
multidisciplinary care teams is recommended. At the
time of initial confirmation of the diagnosis, baseline
assessment, investigations, and initiation of therapy are
recommended. In addition, patient/parent education is
recommended. When a patient presents with
complications necessitating hospital admission, these
objectives can be obtained during hospitalization.
Follow-up out-patient visits are scheduled at two- to
three-monthly intervals. Hospital admission is required
for treatment of acute pulmonary exacerbation and
severe complications.
Patients are monitored in the CF clinic every two to
three months to achieve the following goals:
? maintenance of growth and development;
? maintenance of lung function as nearly normal as
possible using clinical assessment, pulmonary
function testing, and oxyhemoglobin saturation;
? intervention and retardation of the progression of
lung disease via appropriate use of antibiotics,
bronchodilators, and airway clearance techniques;
? clinical assessment to monitor gastrointestinal tract
involvement and presence of malabsorption, and to
provide enzyme and nutrition supplementation;
? monitoring for complications and their treatment;
and
? addressing psychosocial issues.
Patient and family education to provide counseling at
the time of initial diagnosis should include information
regarding inheritance and risk for recurrence in
subsequent pregnancies. Initial and subsequent visits are
used to instruct patients and parents regarding
appropriate airway clearance technique and the need
for chest physical therapy.These visits are also used to
instruct patients and parents regarding the use of
various drug delivery devices, such as spacers and
nebulizers, and methods for modifying the pancreatic
enzyme dosage,as well as to discuss when to contact CF
center personnel. CF clinic personnel should be
prepared to counsel families regarding the impact of the
diagnosis on the emotional life of parents, siblings, and
members of the extended family.
Surgical therapy may be required for the treatment of
respiratory complications such as pneumothorax,
massive recurrent or persistent hemoptysis, nasal polyps,
and persistent or chronic sinusitis. Gastrointestinal tract
complications, such as meconium ileus, intussusception,
gastrostomy tube placement for supplemental feeding,
and rectal prolapse, also require surgical therapy. Lung
transplant is indicated for the treatment of ESLD.
Prognosis
Prognosis in patients with CF has improved over the
last few decades, but it is still a life-limiting disease and
a cure remains elusive. Current median survival age is
35 years. Marked heterogeneity exists in disease severity
and progression. Severity of pulmonary disease
determines prognosis and ultimate outcome. With
current treatment strategies, 80% of patients should
reach adulthood. a73
The Pathophysiology, Diagnosis, and Investigation of Cystic Fibrosis
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