Cystic Fibrosis More than just mucus

Cystic FibrosisBest Practices

Diane Hanfelt-Goade MDDirector, Adult CF Center

128 year-old gentleman with cystic fibrosis, genotype F508 homozygousDiagnosed as an infant with meconium ileusFollowed every 3 months in CF clinicColonization with Pseudomonas aeruginosa and Staphylococcus aureusHistory of staph schleiferi and aspergillus tares. Called with increasing cough and SOB for three weeks

Case presentation

1. Moderate to severe lung dysfunction2.Pancreatic insufficiency.3.Chronic sinusitis, nasal polyps4.Allergic rhinitis.5.Impaired glucose tolerance. 6.Reactive airway disease.7.History of hiatal hernia.8.History of H. pylori9.Sleep apnea10.Low body mass index.

Problem list

1.Pulmozyme 2.5 milligrams inhaled once daily.2.7% hypertonic saline inhaled once per day.3.Oxygen 2 liters nocturnally.4.Vest once per day5.Acapella once or twice per day.6.Tobi 300 milligrams inhaled, 28 days on, 28 days off. This is an off cycle.7.Aztreonam 75 milligrams inhaled three times a day 28 days on, 28 days off. 8.Azithromycin 500 milligrams by mouth Monday, Wednesday, Friday.9.Ultrase MT18s, 8-9 with meals and 4-5 with snacks.10.Ensure three cans daily.11.Multivitamin one tablet by mouth once daily.12.Calcium 600 milligrams with 125 of D, once daily.13.Flonase 0.5 %, two sprays per nostril once or twice per day.14. AquADEK, 2 tablet by mouth daily15.Scan Dical as needed. 16.Vitamin D 50,000 international units reports he took for 8 to 10 days 17.Vitamin A, dosage unknown, one tablet by mouth every day. 18.Vitamin E 400 international units one by mouth every day. 19.Zyrtec 10 mg by mouth as needed for allergies.20. Spiriva 18 micrograms inhaled once daily. 21.Saline nasal washes as needed. 22.ProAir 90 micrograms inhaled two to three puffs prior to therapy and as needed.23.Advair HFA 2 puffs twice daily.

Medications and treatments:

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 diseaseAutosomal recessive inheritanceCause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)chromosome 7 codes for a c-AMP regulated chloride channelWhat is cystic fibrosis (CF)?Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

6Many functions still under investigation----CFTROne or more clinical features of CF PLUSTwo CF mutations on genetic testing ORTwo positive quantative pilocarpine iontophoresis sweat chloride values ORAn abnormal nasal transepithelial potential difference value

Diagnosis of cystic fibrosisCystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

1st Descriptions17th Century European folkloreA child that tastes salty when kissed will soon die.Thought to be hexed/bewitched

18th Century Case DescriptionsCases of children with severe malnourishment, steatorrhea, meconium ileus

Quinton PM. Phys Rev;1999;79:S3-S22. www.cysticfibrosismedicine.com

Clinical Description1943 Dr. Stanely FarberMucoviscidosisMultisystem diseaseMajor manifestationsChronic bronchopulmonary infectionsMalabsorption and steatorrheaGrowth Failure

Farber S. Arch Pathol 1944;37:283-250.

History1948 Dr. Paul di Sant AgneseHigh chloride/sodium in sweat CF patientsStandardization of sweat test by 1959

1954 1st comprehensive CF center

Cystic fibrosis transmembrane conductance regulator (CFTR) geneThe CFTR gene is located on the long arm of chromosome 7.There are 1522 mutations in CFTR listed on the mutation database (http://www.genet.sickkids.on.ca/cftr/)The most common mutation is F508-70% CF alleles in caucasians.1Causes loss of aa phenylalanine at position 508 in protein

http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/cftr.shtml1. Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of PulmonaryInfections in Cystic Fibrosis. AJRCCM 168 (918-951);2003.

11Delta f508 causes loss of the amino acid phenylalanine located at position 508 in the protein CFTR

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.CFTR functions as a regulated chloride channelAlso regulates the activity of other chloride and sodium channels at the cell surface

Cilia do not beat well when PCL volume is depletedMucins are not diluted and cannot be easily swept up the airway Mucus becomes concentratedResults in increased adhesion to airway surfacePromotes chronic infectionAirway surface liquid low volume hypothesis and consequencesDonaldson,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 bacteriaClearance of mucus depends on Ciliary functionMucin secretion Volume of airway surface liquid (ASL) Forms periciliary liquid layerDilutes mucus---facilates entrapment of bacteria and clearanceOptimal volume of ASL regulated by Na+ absorption and Cl- secretionAirway surface liquid low volume hypothesisDonaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

CFTR and Airway Surface Liquid

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.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 http://www.cff.orgBurden of CF

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 yearsatypical disease

UNM Adult care center has approx 66 patientsBurden of CF (continued)http://www.cff.org

Overall trend is improved survival

Female survival worse than male between 2-20 years of age1

35% of patients are older than 18 years of age2

Median survival 36.8 years31930s life expectancy was about 6 months2

The impact of usual adult diseases in CF is virtually unknown

CF Survival1.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. 3.www.cff.org/news/general_news

Chronic SinusitisChronic pulmonary infectionsEndobronchial diseaseGI diseaseNutritional deficienciesLiver diseaseCFRD, pancreatic dysfunctionObstructive azospermia

CF clinical manifestations

Chronic infection with CF pathogens Endobronchial diseaseCough/sputum productionAir obstruction---wheezing; evidence of obstruction on PFTsChest x-ray anomaliesDigital ClubbingSinus diseaseNasal PolypsCT or x-ray findings of sinus diseaseChronic Sino-Pulmonary DiseaseCystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

Endobronchial disease

HyperinflationPeribronchial cuffingBronchiectasisDiffuse fibrosis AtelectasisFrom: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

Nasal Polyps

Benign lesions in nasal airwayIf large enough, can be associated with significant nasal obstruction, drainage, headaches, snoringLikely associated with chronic inflammationMay need surgical interventionHigh recurrence rateFrom: http://www.emedicine.com/ped/topic1550.htm

Intestinal abnormalityMeconium ileusDistal intestinal obstruction syndrome (DIOS)Rectal prolapseHepatobiliary diseaseFocal biliary cirrhosisMultilobular cirrhosisPancreatic endocrine dysfunctionCystic fibrosis related diabetes

GI disease

Pancreatic insufficiencyAutopsy of malnourished infants--1938--- cystic fibrosis of the pancreas---mucus plugging of glandular ducts1Nutritional deficiencyDavis, 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 ducts2Pancreatic enzymes stay in ducts and are activated intraductallyAutolysis of pancreasInflammation, calcification, plugging of ducts, fibrosis

MalabsorptionFailure to thriveFat soluble vitamin deficiencyNutritional deficiencyDavis, 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.

ComplicationsEndocrineGlucose intolerance/CFRDReduction in insulin secretion due to pancreatic damageInsulin resistance related to infection and CF exacerbationsAssociated with accelerated pulmonary decline and increased mortalityArthropathy (2-9%)Osteopenia/osteoporosis

Focal inspissation of bileObstructs biliary ductulesSecond leading cause of death in CF1Prevalence 9-37%1Spectrum of disease increased liver enzymes biliary cirrhosis portal hypertension

Cystic fibrosis related liver disease1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.

27Ursodiol increases bile flow {02} . In chronic cholestatic liver disease, ursodiol appears to reduce the detergent properties of the bile salts, thus reducing their cytotoxicity. Also, ursodiol may protect liver cells from the damaging activity of toxic bile acids (e.g., lithocholate, deoxycholate, and chenodeoxycholate), which increase in concentration in patients with chronic liver disease Clinically---hypochloremic metabolic alkalosisCFTR on luminal side of sweat ductChloride goes in from lumen via CFTR and out to blood by other transportersSodium goes in via ENaCDefective CFTR---Na and Cl- movement and reabsoprtion into lumen impeded Electrolyte abnormalityGoodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005

PathophysiologyMurphy TM and Rosenstein BJGenetic and Protein DefectAbnormal Salt and Water TransportPersistent Airway Infection, invasion of neutrophilsAccumulation of Leukocyte-Derived DNAand Elastase-Rich SecretionsExacerbations of InfectionsAirway ObstructionProgressive Lung DestructionEarly Death

Modify phenotype and disease expression in CFTGF-beta 1potent suppressor of T cell activationcan 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 diseaseMBL Mannose-binding lectin important component of the complement systemdeficiencies increase the risk for pyogenic infectionsIn CF, variant MBL alleles associated with reduced lung function, increased risk for complex infections, and early deathpolymorphisms of TNF-aincrease susceptibility to Ps. aeruginosa infection and contribute to the clinical manifestations of CFGENE MODIFIERS

Individuals with CF are living longermost 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 spanWith prolonged infection, P. aeruginosa converts to a mucoid phenotype by the production of alginateConversion to mucoidy is associated with worsening lung functionincrease in the prevalence of several potentially pathogenic microorganisms in CFInfections in CF

Infection

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

32Age-specific prevalence of airway infections in patients with CF. Organisms reported to the U.S. Cystic Fibrosis Patient Registry, 2001 Early infections in CF airways are most frequently caused by S. aureus and H. influenzae. natural history study of patients with CF in the first 3 years of life, the mean age of detection of an antibody response to P. aeruginosa was approximately 15 months, whereas the mean ages of first positive upper and lower airway culture were approximately 21 and 23 months Burkholderia cepacia complexB. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, deathChronic cepacia infectiondecreased lung function and increased mortalitySeveral closely related species termed genomovars1III has been associated with more severe disease

Holmes, A, Govan, J, andGoldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health?Emerging Infectious Diseases. 4(2):221-227; 19981. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

33Nine recognized genomovarsMost common are II, III, VNTM in about 13% of patients75% is MACTreat if criteria for disease is met: pulm nodules, deteriorating functionAspergillusInfection vs. colonizationABPA Nationwide, MRSA increased from 2.1 percent in 1996 to 21.2 percent in 2007

Other infections

Increased coughIncreased sputum production or chest congestionIncreased dyspnea with exertionIncreased fatigueDecreased appetiteIncreased respiratory rate or dyspnea at restChange in sputum appearanceFever (present in a minority of patients)Absenteeism from school or workIncreased nasal congestion or drainageReductions in FEV1Reduction of greater than 10% = admission

ACUTE PULMONARY EXACERBATIONS

Admitted for 14 daysantibiotics chest phsyiotherapy and inhaled meds 4 times dailyAggressive nutrition, physical therapyBlood sugar controlAfter 14 days of treatment, patients receiving antibiotics had greater increases in several pulmonary function measures than those treated with placeboStandard of care, so covered by most insurancesMajority of patients with some second payer coverageACUTE PULMONARY EXACERBATIONS

Directed to culture resultsRecognize that multiple species often presentWe are now using synergy data as wellMost common: tobra + anti-PA ES PCN (zosyn) or 3rd or 4th gen cephThe clearance of aminoglycosides is accelerated in CF patients Once daily dosing endorsed by the CFFPatients hypermetabolic, increased hepatic clearance of sulfonamidesNo changes: vanco, quinolones? Absorption of oral antibioticsACUTE PULMONARY EXACERBATIONS: antibiotic considerations

18 months: data on 65 patients with at least one positive cultureMost with persistent positive culturesMost with polymicrobial infections52 PA90% mucoidIncreasing MDRO now almost 50% 18 MSSA and PA5 MRSA and PAUNM data

23 MSSA14 MRSA2 B. cepacia patientsMSSA, PA, B. cepaciaMRSA , B. cepaciaAspergillus fumigatus, B. cepcia 4 Stenotrophomonas1 small colony variant4 H. fluUNM data

Kleb pneumoFlavobacterium meningosepticumAchromobacterMorganellaAspergillus fumigatusAspergillus terusScedosporium apiospermumNocarida transvalensis R to bactrim

UNM data

CF Foundation guidelinesUNM is a certified care centerCertification requires demonstration of an integrated team approachCompliance with guidelines and standards of careStandards developed using evidence based care practices, committee reviewCurrent guidelines and supporting data at the CF Foundation websitehttp://www.cff.org/treatments/CFCareGuidelines

CF standard of care

Diane Hanfelt-Goade, adult clinic directorCharles Gallegos CFNP, CF care specialistLinda Reineke, nutritionist and diabetes educatorBill Demary, resp therapyFelisha Martinez, social workUNM CF Care Team

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 weighthe quality of evidence and the potential harms and benefits indetermining recommendations (Table 1)Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary ExacerbationsPatrick 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*Am. J. Respir. Crit. Care Med. 2009 Nov;180(9):802-8. Epub 2009 Sept. 3

Although they did not meet criteria for this systematicreview, there are observational studies that suggest betteroutcomes for patients treated in a hospital than for thosetreated at home (10, 11).If there is any doubt, admission to the hospital is thesuggested option. This may be particularly relevant for patientswith comorbidities that complicate care and for patients withmore severe exacerbations who may be too fatigued or in toomuch distress to be able to perform the therapies adequately.For example, nutritional needs, elevated in most patients withCF, are even greater during an exacerbation (8)

Chest physiotherapyPostural drainage and percussionP.E.P valve, Acapella valve, Flutter valveHigh frequency chest wall oscillationAlbuterolBronchodilationIncrease ciliary efficiencyDornase alpha/recombinant DNase (pulmozyme)Breaks down excess DNA from neutrophils and bacteria Hypertonic Saline by nebulizationThins secretions

Treatment: Airway clearance

Saiman et al., 2003 double blind placebo controlled trial of azithromycin185 patients randomized to receive 3 times weekly azithromycin or placeboImprovements in lung function, weight, and number of pulmonary exacerbations (decreased courses of antibiotics and days in hospital)

Treatment: AzithromycinSaiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.

Follow nutrition parameters closelyPancreatic enzymesVitamin supplementationFat soluble vitamins ADEK dailyOther nutritional supplementationTube feedingsHigh calorie supplemental shakes, formulasTreatment: Nutrition

Initiate if have malabsorption historyFecal fatFecal elastaseMay need H2 blocker or PPI to activate enteric coated enzymeEnzymes with meals and snacks, usually keep at bedsidePatients bring their own, as hospital typically does not carry the branded enzymesFibrosing colonopathyStrictures in the colon associated with high dose enzyme use (enzyme gets to colon and causes damage leading to scarring/stricture)

Treatment: Pancreatic enzymes

UrsodiolIncreased bile flowDecrease toxicity of bile acidsSclerotherapy, portosystemic shuntsLiver transplantation---only curative treatment for portal hypertension

Treatment: Cystic fibrosis related liver disease

Quality of lifeFrequent hospitalizationsTime spent on therapiesMorbidity from diseaseRestrictions secondary to diseaseAdherence to therapiesFamily planningEnd of life issues

Psychosocial 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 approachSummary

Lack of knowledge/info on CF specific careCurrently, CF survival guide on drop down menu in CF order setinterns/residents should use the CF checklist and survival guidethis should become available on the Hospitalist Wiki?

Standard order sets for admission may not applyDVT prophylaxis should not be used as a matter of coursePatients on daily vit K therapyPatients at much higher risk for hemoptysis or bleeding than for clotting

- CF DM educator should take point on CF DMRoutine insulin orders generally not applicable, CFRD different than type 1 DMEndo consult appropriate for anyone on a pump

Best practice questions

We should define a clear procedure for admission of CF "tune upsMay be several days before a bed availableCF team always contact admitting teamInformation not always passed alongCF team always dictates a stat note with reason for admission, order recs

Lack of communication on inpatientsCharles rounds with pulmonary team dailyCharles discusses patients with Diane dailyEntire CF team rounds wed afternoon? Should we round with medicine teams once a week also, or after an admissionResident or Intern should contact Charles to arrange a good time, Monday?

Best practice questions