Transcript Cystic Fibrosis: A disease for a multidiscplinary team

Cystic Fibrosis: A Disease
for a
Multidisciplinary Team
Kim Otsuka, MD
Pediatric Pulmonary Fellow
September 21, 2004
UoA PPC 2004 Workshop Lectures
Objectives





Brief overview of cystic fibrosis (CF)
Review some of the “newer” pulmonary
therapies in CF
Highlight nutritional issues in CF
Highlight psychosocial issues in CF
Highlight respiratory care issues in CF
CF Center Team







Center director
Associate center director
Clinic coordinator
Social worker
Respiratory therapist
Nurse
Registered dietitian
Cystic Fibrosis - A recap

Epidemiology
Most common life-threatening inherited disease
 Autosomal recessive
 Incidence 1:3200 live births (Caucasians)*



Hispanics 1:9200, Blacks 1:15,000, Asians 1:31,000
1:28 Caucasians are carriers

Hispanics 1:48, Blacks 1:61; Asians 1:88
*Adapted from Hamosh A, et al. J Pediatr 1998; 132: 255-259
Genetics

Single gene defect on
chromosome 7


Dicovered in 1989
Cystic fibrosis
transmembrane regulator
(CFTR)


Most common F508
Over 1000 mutations
identified
Zeitlin P, N Engl J Med 2004; 351: 606-8.
Pathophysiology

CFTR mutations affect epithelial cells, thus
affecting:
Airways (sinuses, lungs)
 Pancreas (endocrine and exocrine)
 GI tract (liver/biliary system, intestines)
 Reproductive organs
 Skin

Pulmonary Pathophysiology

2 theories

Composition hypothesis


Airway epithelia regulate the airway surface liquid (ASL)
salt content that is important for lung defense
Volume hypothesis

Airway epithelia regulate the volume of liquid in the
mucus and periciliary liquid layers of ASL for efficient
ciliary mucus interactions and airway clearance.
Pulmonary - Pathophysiology
Ratjen F, Coring G. Lancet 2003; 361: 681-89.
Pulmonary Pathophysiology

CFTR mutation --> abnormal airway surface
microenvironment --> thickened mucus, chronic
infection, chronic inflammation --> damages
airway ---> bronchiectasis, respiratory failure
and often death
Inflammation in CF
Konstan MW, Davis PB. Advanced Drug Delivery Reviews
2002; 54: 1409-1423
Treatment: Anti-inflammatories

Ibuprofen




Konstan et al, NEJM
1995
85 patients




5 - 39 y/o
FEV1 > 60 % predicted
20-30 mg/kg of ibuprofen
peak plasma
concentrations 50-100
mcg/mL
Results
FEV1



-2.17 + 0.57 vs. -3.60 +
0.55 (p=0.02)
weight better in
ibuprofen group
(p=0.02)
Adverse events


No difference between
groups in study
Increased GI hemorrhage
in f/u
Treatment: Anti-inflammatories

Azithromycin






Multicenter US trial
double-blind,
randomized, placebocontrolled trial
185 patients, >6 y/o
FEV1 >30% predicted
weight <40 kg: 250 mg
azithromycin 3x/wk
weight >40 kg: 500 mg
azithromycin 3x/wk

Results





At 24 weeks into study
FEV1 gain 4.77% in
azithromycin group
FEV1 loss -1.77% in
placebo
Improved weight gain
and decreased
hospitalizations in
azithromycin group
Adverse events: nausea,
diarrhea, wheezing
Mucolytics
King M, Rubin BK. Advanced Drug Delivery Review 2002; 54: 1475-90
Pulmozyme®

Dornase alfa





Fuchs, et al 1994
968 patients (youngest 5
y/o)
Randomized, doubleblinded placebo controlled
trial
placebo vs. once or twice
daily DNAse
Results

Improved QOL, health
economics

Pulmonary exacerbations




FEV1 (improved p<0.01)



once daily: RR 0.78 (CI
0.57-1.06; p=0.11)
twice daily: RR = 0.66
(CI 0.48-0.91; p=0.01)
once daily 5.8 + 0.7
twice daily 5.7 + 0.7
Adverse events

Voice alteration, laryngitis,
rash
Antibiotics



Often unable to eradicate the organism
Determining optimal delivery mode for a drug
is difficult
CF patients require higher doses
Altered volume of distribution
 Rapid clearance of drugs

Inhaled Tobramycin (Tobi®)



Ramsey et al, 1999
520 patients, >6 y/o
Tobi 300 mg bid x 28
days q o month x 20
weeks




Decreased density of
pseudomonas
Decreased
hospitalizations
Additive effect with
DNase
Adverse events




Ramsey et al, NEJM 1999; 340: 23-30
Tinnitus
Voice alteration
No hearing loss
No change in kidney
function
Nutritional Issues
Nutritional Issues


Nutrition is closely tied to overall health
Malnutrition in CF associated with
Stunted growth
 Pubertal delay
 Deterioration of lung function
 Early death

ESCF Study




J. Pediatrics 2003
931 patients
3-6 years
Parameters evaluated:
Height, weight, s/sx of lung disease recorded at
age 3 and 6
 Respiratory tract culture < 3 y/o
 1 valid spirometry obtained when stable between
5.5 and 7.5 y/o

Results - age 3
Konstan MW, J. Pediatr 2003; 142:624-30
Results - age 6
Konstan MW, J. Pediatr 2003; 142:624-30
Weight gain improves lung
function by age 6
Konstan MW, J. Pediatr 2003; 142:624-30
Conclusions




Indexes of growth and nutrition at age 3 associated
with lower pulmonary function at age 6
S/sx of lung disease at age 3 are also associated with
lower pulmonary function at age 6
Relative weight loss was associated with worse lung
function
Relative weight gain was associated with improved lung
function
Care team responsibilities



Monitor growth
Provide anticipatory counseling and plan
interventional strategies for those who are
undernourished or are at high risk
Dietitian


Provides discipline-specific expertise needed for
optimal nutritional management
Provide expertise concerning developmental and
behavioral aspects of eating
Nutritional management



Growth and nutritional status monitored every 3
months
Annual pubertal assessment
Especially important times for monitoring
First 12 months after diagnosis
 Birth to 12 months for those diagnosed prenatally or
by GDS
 Peripubertal growth period

Pancreatic Insufficiency



85-90% affected
Malabsorption fats,
protein, and other
nutrients
Diagnostic tests




Treatment



72 hour fecal fat
fecal elastase-1
PS patient re-evaluated
annually
Pancreatic enzyme
supplementation



Improved release with H2
blocker or PPI
Proprietary enzymes better
than generic
Complication: fibrosing
colonopathy
Taurine supplementation
Curcumin
Calorie intake

Greater than RDA for those without CF




Weight goal is 100-110% IBW
Fat intake 35-40%
Protein 15-20%
Supplements
Oral: controversial
 Enteral

The Vitamins

Vitamin A




Vitamin D


15-40% deficient
18% adults deficits in
dark field adaptation
Negative acute phase
reactant (do not draw
with acute illness)
10-40% deficient
Vitamin E

5-10% deficient

Vitamin K



PIVKA-II vs. PT
Essential Fatty Acids
Minerals and
Electrolytes




Calcium
Iron
Zinc
Sodium
Bone monitoring

Children > 8 y/o with
risk factors






Post-organ transplant
End-stage lung disease
Bone fracture with lowimpact activity
Chronic corticosteroid
use
Delayed pubertal
development
Nutritional failure

Screening




DEXA lumbar spine
Annual serum calcium,
phosphorous, intact PTH,
25-hydroxy vit D
Dietary assessment of
calcium and vit D
Treatment


Optimize nutrition and
intake of vit D, K,
calcium
Weight bearing physical
activity
Cystic Fibrosis Related Diabetes

Leading comorbidity associated with CF
Prevalence increased by 173% from 1992-2002
 Prevalence increases with age


3-12% are reported to have diabetes
14% of CF patients >14 years old
 25% of CF patients 35-44 years old



Average age of onset 18-21 y/o
Females > Males
Glucose Intolerance Increases with Age
Moran, et al. J. Pediatrics. 133(1998)
Survival
Analysis of survival
at University of
Minnesota has
demonstrated that
the rapid decline in
survival can be
attributed to females
with CFRD since
males with CFRD
has ~equivalent
suvival rates to males
without CFRD
Finnkelstein et al. . J Pediatr 1988; 112: 373-7
Rate of Decline in Pulmonary Function is
Related to Oral Glucose Tolerance Status
Milla CE et al: Am J Resp Crit Care Med 162:891-5, 2000
Comparison of CFRD with
type 1 and type 2 DM
Type 1
Insulin secretion
Type 2
CFRD
Absent
Insulin
sensitivity
Autoimmunity
Yes
No
No
Age
<20
>40
18-21
Body habitus
Normal
Obese
Slender
Ketoacidosis
Yes
Rare
Rare
Microvascular
Yes
Yes
Yes
Macrovascular
Yes
Yes
No?
Moran T: Mountain West Consortium June 24, 2004
Therapy - CFRD


Treatment: insulin
Control glucose to avoid acute/chronic
complications




FPG 80-120 mg/dl
Post-prandial FSBS with + 30 mg/dl from pre-meal
value
HgA1c < 7%
Maintain optimal nutritional status and growth
 Continue high energy intake
Respiratory Care
Issues
Pulmonary Function Tests





Spirometry
Respiratory rate
Pulse oximetry
Lung volume
Exercise studies
Aerosol Delivery Systems


They are not all equal
2 important
considerations


Volume
Concentration of
therapeutic agent
Airway Clearance



Standard daily therapy for patients with cystic
fibrosis
CF --> viscous airway secretions + poor
clearance --> airway obstruction and infection -> airway injury, fibrosis --> bronchiectasis
Goal: enhance clearance of airway secretions
Airway Clearance
Wagener JS, Headley AA. Respir Care 2003; 48: 234-45
Airway Clearance

Chest physiotherapy





Accepted standard
Goal move peripheral
mucus into central
airways



Active cycle breathing
Autogenic drainage
PEP and flutter


low, high pressure
oscillating
Intrapulmonary
percussive ventilation
High-Frequency Chest
Compression


Shears mucus away from
airways
Modifies viscoelastic
properties of mucus
Exercise
Typical Day Airway
Clearance/Aerosols





Albuterol 2x/day (15-20 minutes each)
Dnase 1x/day (15-20 minutes)
Inhaled tobramycin 2x/day (15-20 minutes)
Chest clearance 2x/day (20-30 minutes)
Step up to 3-4x/day will illnesses
Psychosocial Issues
Social Issues


Address social concerns every 3 months
Complete assessment by an MSW or
psychologist should be performed annually
including
Changes in family structure and coping
 School and work performance
 Participation in age appropriate activities
 Developmental and emotional issues
 Vocational training and preparation for adult life

Social Issues

Other
Concerns about CF patient care and understanding
of disease manifestations and treatment
 Compliance with treatment regimens
 Financial issues related to the illness
 Family planning when reaching reproductive age

Psychosocial Aspects

WHO definition of health
“A State of complete physical, mental, and social
well being and not merely the absence of disease
or infirmity”

Health related quality of life (HRQOL)
Physical health
 Mental health
 Social function
 Role function
 General health perceptions

Psychosocial Aspects


Overall psychosocial
function is good
Problem areas



Exacerbations - neg
impact on general and
physical health
Increased vulnerability
to stress of life
More dysfunction seen
in families with older
patients



Lower PFT’s had a
greater impact on the
parents than the
patients
Patients >12 years
increased distress with
hospitalization
Compliance of
treatment regimens
improved in mother
with less frequent social
contacts and less
satisfactory marital
relationships
Psychosocial Aspects

Intellectual function distributed normally


Inversely related to age
Academic function distributed normally

No changes with age
Lower levels of academic and intellectual
functioning in lower SES classes
 Age and SES account for 21% and 43% of variance
in level of functioning

Risk Behaviors

Cystic fibrosis patients vs. age-matched
adolescent peers
Alcohol use 45.5% vs. 63.1%
 Cigarettes 21.1% vs 53.3%
 Marijuana use 9.7% vs 29.4%
 Cocaine and other injectable drugs 2.6% vs. 5.7%

Risk Behaviors

H/O sexually activity 28.3% vs. 46.4%


No difference in risky sexual behaviors: condom use,
no contraception, and pregnancy
Tendency for improved health promoting
behaviors

Seat belt use, bicycle helmets
Take Home Points


CF management requires the coordinated efforts
of a CF care team
Growth and nutrition is critical for pulmonary
health


“Breakfast is as important as morning CPT”
All adolescents need risk behavior assessments