Diane Hanfelt-Goade MD Director, Adult CF Center       28 year-old gentleman with cystic fibrosis, genotype Δ F508 homozygous Diagnosed as an infant with meconium.

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Transcript Diane Hanfelt-Goade MD Director, Adult CF Center       28 year-old gentleman with cystic fibrosis, genotype Δ F508 homozygous Diagnosed as an infant with meconium.

Diane Hanfelt-Goade MD
Director, Adult CF Center
28 year-old gentleman with cystic fibrosis,
genotype Δ F508 homozygous
Diagnosed as an infant with meconium ileus
Followed every 3 months in CF clinic
Colonization with Pseudomonas aeruginosa and
Staphylococcus aureus
History of staph schleiferi and aspergillus tares.
Called with increasing cough and SOB for three
1. Moderate to severe lung dysfunction
2. Pancreatic insufficiency.
3. Chronic sinusitis, nasal polyps
4. Allergic rhinitis.
5. Impaired glucose tolerance.
6. Reactive airway disease.
7. History of hiatal hernia.
8. History of H. pylori
9. Sleep apnea
10. Low body mass index.
Pulmozyme 2.5 milligrams inhaled once daily.
7% hypertonic saline inhaled once per day.
Oxygen 2 liters nocturnally.
Vest once per day
Acapella once or twice per day.
Tobi 300 milligrams inhaled, 28 days on, 28 days off. This is an off cycle.
Aztreonam 75 milligrams inhaled three times a day 28 days on, 28 days off.
Azithromycin 500 milligrams by mouth Monday, Wednesday, Friday.
Ultrase MT18s, 8-9 with meals and 4-5 with snacks.
Ensure three cans daily.
Multivitamin one tablet by mouth once daily.
Calcium 600 milligrams with 125 of D, once daily.
Flonase 0.5 %, two sprays per nostril once or twice per day.
AquADEK, 2 tablet by mouth daily
Scan Dical as needed.
Vitamin D 50,000 international units reports he took for 8 to 10 days
Vitamin A, dosage unknown, one tablet by mouth every day.
Vitamin E 400 international units one by mouth every day.
Zyrtec 10 mg by mouth as needed for allergies.
Spiriva 18 micrograms inhaled once daily.
Saline nasal washes as needed.
ProAir 90 micrograms inhaled two to three puffs prior to therapy and as needed.
Advair HFA 2 puffs twice daily.
Pulmonary function tests
FVC of 2.27 (39%),
FEV1 1.30 (27%),
FEF 25-75% is 0.52 (11%),
RV/TLC % of 46
A multisystem disease
Autosomal recessive inheritance
Cause: mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR)
◦ chromosome 7
◦ codes for a c-AMP regulated chloride channel
Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.
One or more clinical features of CF
Two CF mutations on genetic testing
Two positive quantative pilocarpine iontophoresis
sweat chloride values
An abnormal nasal transepithelial potential
difference value
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
1st Descriptions
17th Century European folklore
◦ “A child that tastes salty when kissed will soon
◦ Thought to be hexed/bewitched
18th Century Case Descriptions
◦ Cases of children with severe malnourishment,
steatorrhea, meconium ileus
Quinton PM. Phys Rev;1999;79:S3-S22. www.cysticfibrosismedicine.com
Clinical Description
1943 Dr. Stanely Farber
◦ “Mucoviscidosis”
◦ Multisystem disease
 Major manifestations
 Chronic bronchopulmonary infections
 Malabsorption and steatorrhea
 Growth Failure
Farber S. Arch Pathol 1944;37:283-250.
1948 Dr. Paul di Sant’ Agnese
◦ High chloride/sodium in sweat CF patients
◦ Standardization of sweat test by 1959
1954 1st comprehensive
CF center
The CFTR gene is located on the
long arm of chromosome 7.
There are 1522 mutations in
CFTR listed on the mutation
The most common mutation is
Δ F508-70% CF alleles in
Causes loss of aa phenylalanine
at position 508 in protein
1. Gibson, RL, Burns, JL, and Ramsey, BW.
Pathophysiology and Management of Pulmonary
Infections in Cystic Fibrosis. AJRCCM 168 (918-951);
CFTR functions as a regulated chloride channel
Also regulates the activity of other chloride and
sodium channels at the cell surface
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary
Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Cilia do not beat well when PCL volume is depleted
Mucins are not diluted and cannot be easily swept
up the airway
Mucus becomes concentrated
 Results in increased adhesion to airway surface
 Promotes chronic infection
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
Mucus---helps clear airway of bacteria
Clearance of mucus depends on
◦ Ciliary function
◦ Mucin secretion
◦ Volume of airway surface liquid (ASL)
 Forms periciliary liquid layer
 Dilutes mucus---facilates entrapment of
bacteria and clearance
 Optimal volume of ASL regulated by Na+
absorption and Cl- secretion
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
Most common “life-shortening” recessive genetic
disease in Caucasians
◦ 1:3,500 newborns in the US
◦ 1 in 10,500 Native Americans
◦ 1 in 11,500 Hispanics
◦ 1 in 14,000 to 17,000 African Americans
◦ 1 in 25,500 Asians
About 30,000 people affected in United States
>10,000,000 people carriers of mutant CFTR
80% cases diagnosed by age 3
Almost 10% diagnosed ≥18 years
◦ “atypical disease”
UNM Adult care center has approx 66 patients
Overall trend is improved survival
Female survival worse than male between 2-20 years of
35% of patients are older than 18 years of age2
Median survival 36.8 years3
The impact of usual adult diseases in CF is virtually
• 1930s life expectancy was about 6 months2
1.Goss, CH and Rosenfeld, M. Update on cystic fibrosis epidemiology. Current Opinion in
Pulmonary Medicine. 10:510-514; 2004.
2. Davis, P. Cystic Fibrosis Since 1938. AJRCCMss. Doi: 10.1164/rccm.200505-840OE; 2005.
Chronic Sinusitis
Chronic pulmonary infections
Endobronchial disease
GI disease
Nutritional deficiencies
Liver disease
CFRD, pancreatic dysfunction
Obstructive azospermia
Chronic infection with CF pathogens
Endobronchial disease
– Cough/sputum production
– Air obstruction---wheezing; evidence of
obstruction on PFTs
– Chest x-ray anomalies
– Digital Clubbing
Sinus disease
– Nasal Polyps
– CT or x-ray findings of sinus disease
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
Diffuse fibrosis
From: http://www.emedicine.com/
Benign lesions in nasal
If large enough, can be
associated with
significant nasal
obstruction, drainage,
headaches, snoring
Likely associated with
chronic inflammation
May need surgical
High recurrence rate
Intestinal abnormality
◦ Meconium ileus
◦ Distal intestinal obstruction syndrome (DIOS)
◦ Rectal prolapse
Hepatobiliary disease
◦ Focal biliary cirrhosis
◦ Multilobular cirrhosis
Pancreatic endocrine dysfunction
◦ Cystic fibrosis related diabetes
Pancreatic insufficiency
– Autopsy of malnourished infants--1938--“cystic fibrosis of the pancreas”---mucus
plugging of glandular ducts1
1. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
– Chloride impermeability affects HCO3- secretion
and fluid secretion in pancreatic ducts2
• Pancreatic enzymes stay in ducts and are
activated intraductally
 Autolysis of pancreas
 Inflammation, calcification, plugging of ducts,
– Malabsorption
• Failure to thrive
• Fat soluble vitamin deficiency
1. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.
◦ Glucose intolerance/CFRD
 Reduction in insulin secretion due to pancreatic
 Insulin resistance related to infection and CF
 Associated with accelerated pulmonary decline
and increased mortality
◦ Arthropathy (2-9%)
◦ Osteopenia/osteoporosis
Focal inspissation of bile
◦ Obstructs biliary ductules
Second leading cause of death in CF1
Prevalence 9-37%1
Spectrum of disease
◦ increased liver enzymes
◦ biliary cirrhosis
◦ portal hypertension
1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF.
European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.
Clinically---hypochloremic metabolic alkalosis
– CFTR on luminal side of sweat duct
• Chloride goes in from lumen via CFTR and
out to blood by other transporters
• Sodium goes in via ENaC
• Defective CFTR---Na and Cl- movement and
reabsoprtion into lumen impeded
Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport.
Adv Physiol Educ. 29 (79-82); 2005
Genetic and Protein Defect
Abnormal Salt and Water Transport
Persistent Airway Infection, invasion of neutrophils
Accumulation of Leukocyte-Derived DNA
and Elastase-Rich Secretions
Exacerbations of Infections
Airway Obstruction
Progressive Lung Destruction
Early Death
Murphy TM and Rosenstein BJ
Modify phenotype and disease expression in CF
TGF-beta 1
◦ potent suppressor of T cell activation
◦ can decrease T cell proliferation and cytokine production
◦ In a study of 808 patients w delta F 508 mutation,
polymorphisms in the TGF-beta 1 gene were associated with more
severe CF lung disease
MBL — Mannose-binding lectin
◦ important component of the complement system
◦ deficiencies increase the risk for pyogenic infections
◦ In CF, variant MBL alleles associated with reduced lung function,
increased risk for complex infections, and early death
polymorphisms of TNF-a
◦ increase susceptibility to Ps. aeruginosa infection and contribute
to the clinical manifestations of CF
Individuals with CF are living longer
most common cause of death in CF is respiratory failure
secondary to pulmonary infection.
Pseudomonas aeruginosa and Burkholderia cepacia complex
are the pathogens most commonly associated with a
shortened life span
With prolonged infection, P. aeruginosa converts to a mucoid
phenotype by the production of alginate
Conversion to mucoidy is associated with worsening lung
increase in the prevalence of several potentially pathogenic
microorganisms in CF
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary
Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Holmes, A, Govan, J, and
Goldstein, R. Agricultural
Use of Burkholderia
(Pseudomonas) cepacia:
A Threat to Human
Emerging Infectious
Diseases. 4(2):221-227;
B. cepacia syndrome:
fevers, rapidly progressive
necrotizing pneumonia,
Chronic cepacia infection—
decreased lung function
and increased mortality
Several closely related
species termed
– III has been associated
with more severe disease
1. Gibson, RL, Burns, JL, and Ramsey, BW.
AJRCCM 168 (918-951); 2003.
NTM in about 13% of patients
◦ 75% is MAC
◦ Treat if criteria for disease is met: pulm nodules,
deteriorating function
◦ Infection vs. colonization
Nationwide, MRSA increased from 2.1 percent in
1996 to 21.2 percent in 2007
Increased cough
Increased sputum production or chest congestion
Increased dyspnea with exertion
Increased fatigue
Decreased appetite
Increased respiratory rate or dyspnea at rest
Change in sputum appearance
Fever (present in a minority of patients)
Absenteeism from school or work
Increased nasal congestion or drainage
Reductions in FEV1
◦ Reduction of greater than 10% = admission
Admitted for 14 days
◦ antibiotics
◦ chest phsyiotherapy and inhaled meds 4 times daily
◦ Aggressive nutrition, physical therapy
◦ Blood sugar control
After 14 days of treatment, patients receiving antibiotics had
greater increases in several pulmonary function measures
than those treated with placebo
Standard of care, so covered by most insurances
Majority of patients with some second payer coverage
Directed to culture results
Recognize that multiple species often present
◦ We are now using synergy data as well
Most common: tobra + anti-PA ES PCN (zosyn) or 3rd or 4th
gen ceph
The clearance of aminoglycosides is accelerated in CF
◦ Once daily dosing endorsed by the CFF
Patients hypermetabolic, increased hepatic clearance of
No changes: vanco, quinolones
? Absorption of oral antibiotics
18 months: data on 65 patients with at least
one positive culture
◦ Most with persistent positive cultures
◦ Most with polymicrobial infections
52 PA
90% mucoid
Increasing MDRO – now almost 50%
18 MSSA and PA
5 MRSA and PA
2 B. cepacia patients
◦ MSSA, PA, B. cepacia
◦ MRSA , B. cepacia
◦ Aspergillus fumigatus, B. cepcia
4 Stenotrophomonas
◦ 1 small colony variant
4 H. flu
Kleb pneumo
Flavobacterium meningosepticum
Aspergillus fumigatus
Aspergillus terus
Scedosporium apiospermum
Nocarida transvalensis – R to bactrim
CF Foundation guidelines
 UNM is a certified care center
◦ Certification requires demonstration of an
integrated team approach
◦ Compliance with guidelines and standards of care
 Standards developed using evidence based care
practices, committee review
 Current guidelines and supporting data at the CF
Foundation website
 http://www.cff.org/treatments/CFCareGuidelines
Diane Hanfelt-Goade, adult clinic director
Charles Gallegos CFNP, CF care specialist
Linda Reineke, nutritionist and diabetes educator
Bill Demary, resp therapy
Felisha Martinez, social work
Cystic Fibrosis Pulmonary Guidelines: Treatment of
Pulmonary Exacerbations
Patrick A. Flume1, Peter J. Mogayzel, Jr.2, Karen A. Robinson3, Christopher H. Goss4,
Randall L. Rosenblatt5, Robert J. Kuhn6, Bruce C. Marshall7, and the Clinical Practice
Guidelines for Pulmonary Therapies Committee*
“A systematic review was performed addressing a series of questions related
to treatment of pulmonary exacerbations. For each question,
the body of evidence was evaluated by the full Committee. Recommendations
were drafted using the U.S. Preventive Services Task Force
(USPSTF) grading scheme, which provides a mechanism to weigh
the quality of evidence and the potential harms and benefits in
determining recommendations (Table 1)”
Am. J. Respir. Crit. Care Med. 2009 Nov;180(9):802-8. Epub 2009 Sept. 3
Although they did not meet criteria for this systematic
review, there are observational studies that suggest better
outcomes for patients treated in a hospital than for those
treated at home (10, 11).
If there is any doubt, admission to the hospital is the
suggested option. This may be particularly relevant for patients
with comorbidities that complicate care and for patients with
more severe exacerbations who may be too fatigued or in too
much distress to be able to perform the therapies adequately.
For example, nutritional needs, elevated in most patients with
CF, are even greater during an exacerbation (8)
Chest physiotherapy
◦ Postural drainage and percussion
◦ P.E.P valve, Acapella valve, Flutter valve
◦ High frequency chest wall oscillation
◦ Bronchodilation
◦ Increase ciliary efficiency
Dornase alpha/recombinant DNase (pulmozyme)
◦ Breaks down excess DNA from neutrophils and bacteria
Hypertonic Saline by nebulization
◦ Thins secretions
Saiman et al., 2003 double blind placebo controlled
trial of azithromycin
◦ 185 patients randomized to receive 3 times
weekly azithromycin or placebo
◦ Improvements in lung function, weight, and
number of pulmonary exacerbations (decreased
courses of antibiotics and days in hospital)
Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with
Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.
Follow nutrition parameters closely
Pancreatic enzymes
Vitamin supplementation
◦ Fat soluble vitamins ADEK daily
Other nutritional supplementation
◦ Tube feedings
◦ High calorie supplemental shakes, formulas
Initiate if have malabsorption history
◦ Fecal fat
◦ Fecal elastase
May need H2 blocker or PPI to activate enteric
coated enzyme
Enzymes with meals and snacks, usually keep at
Patients bring their own, as hospital typically does
not carry the branded enzymes
Fibrosing colonopathy
◦ Strictures in the colon associated with high dose
enzyme use (enzyme gets to colon and causes
damage leading to scarring/stricture)
◦ Increased bile flow
◦ Decrease toxicity of bile acids
Sclerotherapy, portosystemic shunts
Liver transplantation---only curative treatment for
portal hypertension
Quality of life
◦ Frequent hospitalizations
◦ Time spent on therapies
◦ Morbidity from disease
◦ Restrictions secondary to disease
Adherence to therapies
Family planning
End of life issues
CF is a genetic disorder that most commonly
results in chronic pulmonary infections and issues
related to pancreatic insufficiency
Ultimately, the majority of patients still die from
respiratory failure due to chronic infections
Appropriate treatment is complex and requires a
team approach
Lack of knowledge/info on CF specific care
Standard order sets for admission may not apply
- CF DM educator should take point on CF DM
◦ Currently, “CF survival guide” on drop down menu in CF order set
◦ interns/residents should use the CF checklist and survival guide
◦ this should become available on the Hospitalist Wiki?
◦ DVT prophylaxis should not be used as a matter of course
◦ Patients on daily vit K therapy
◦ Patients at much higher risk for hemoptysis or bleeding than for
◦ Routine insulin orders generally not applicable, CFRD different than type
1 DM
◦ Endo consult appropriate for anyone on a pump
We should define a clear procedure for admission of CF "tune
◦ May be several days before a bed available
◦ CF team always contact admitting team
◦ Information not always passed along
◦ CF team always dictates a stat note with reason for
admission, order recs
Lack of communication on inpatients
◦ Charles rounds with pulmonary team daily
◦ Charles discusses patients with Diane daily
◦ Entire CF team rounds wed afternoon
◦ ? Should we round with medicine teams once a week also,
or after an admission
◦ Resident or Intern should contact Charles to arrange a good
time, Monday?