Cystic Fibrosis: Now a Multisystem Disease of Adolescence and Adulthood

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Cystic Fibrosis Now a Multisystem Disease of
Adolescence and Adulthood

• Andrew Bush MD FRCP FRCPCH
• Imperial School of Medicine
• Royal Brompton Hospital

Email a.bush_at_rbht.nhs.uk
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CF Multisystem, Adult Disease

• How Has this come about?
• Late diagnosis of mild phenotypes
• Effective modern treatment
• What are the consequences?
• Disease issues
• Iatrogenic issues
• Summary and Conclusions

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Late diagnosis of CF 15
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CF Diagnosis in Adolescence and Adult Life - 1

• Bronchiectasis, atypical asthma, chronic
  productive cough
• Atypical asthma
• Male infertility
• Acute pancreatitis
• Non-tuberculous mycobacterial infection

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CF Diagnosis in Adolescence and Adult Life - 2

• Nasal polyps, sinusitis (but ASA)
• Diabetes
• Screening (diagnosis in a relative)
• Pseudo-Bartters syndrome
• Hepatomegaly, splenomegaly, variceal haemorrhage

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Sweat electrolytes - CF, normal, borderline
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CF Genotype (gt 1000 Known Mutations)

• What is the pick-up?
• 2 known mutations -69.7
• 1 mutation found only - 23.7
• No mutations found - 6.6
• (N10,998 genotyped, 21,976 alleles)

• What mutations are found?
• DF508 - 68.2
• G542X - 2.3
• G551D - 2.0
• W1282X - 1.3
• N1303K - 1.2
• R553X - 0.9

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Nasal potentials normal, CF, PBA treated
CF more negative baseline, bigger deflection on
blocking ENaC, no response to low
chloride/isoprenaline
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Other Helpful Pointers

• Stool elastase pancreatic status
• Sputum culture esp Staph. Aureus, Ps.
  Aeruginosa, B. Cepacia
• HRCT Scan Bronchiectasis
• BAL Neutrophilic lavage
• Semen analysis azoospermia

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Infection Common CF Bugs
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CF Oral antibiotics

• Prophylaxis
• Need more work
• Avoid cephalosporins
• Treatment
• 2-4 weeks for any isolate of St aureus, H
  Influenza
• Continuous therapy if repeated isolates

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Nebulized antibiotics Indications

• Eradication 1st isolates Ps aer
• Colistin/Ciprofloxacin
• Tobi
• Chronic Ps aer infection Suppressive
• Colistin
• Aminoglycosides (TOBI, iv preparations)
• Other

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Treatment of Ps Aeruginosa

• Proposed Protocol
• Step 1 (1st isolation) - 3/52 ciprofloxacin
  (25-50 mg/kg/day) and colistin 1mU, bd
• Step 2 (gt1 isolation) - double dose colistin
  tds ciprofloxacin 3/52 therapy
• Step 3 (3rd isolation in 6/12) - as Step 3, 3/12
  therapy
• (TOBI?)
• Pediatr Pulmonol 1997 23 330-5

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IV Antibiotics Treatment When?

• N60 patients randomised to prn or 3 monthly
  ivabs
• prn mean 3 course/yr
• Underpowered study

Deaths 4 in regular group vs. 1 in prn
Thorax 2000 55 355-8
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Treatment Where?

• Home Equal
• N58 patient study
• Infection 2002 30 387-91
• N51 paired treatments
• Eur Respir J 1994 7 1640-4

• Hospital Better
• N63 patient study
• Pediatr Pulmonol 1997 24 42-7
• N140 patient study
• 336
• Audit of experience
• Ir J Med Sci 1999 168 25-8

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Cystic Fibrosis Nutrition (1)

• High fat, high calorie diet
• Ensure adequate salt and fluid intake
• Give fat soluble vitamins (A,E,D,K)
• Monitor height, weight, BMI

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Cystic Fibrosis Nutrition (2)

• Pancreatic enzymes (amount, timing)
• Acid reduction strategies if necessary (H2
  blockers, PPIs)
• PEG feeds as needed

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CF Multisystem, Adult Disease

• How Has this come about?
• Late diagnosis of mild phenotypes
• Effective modern treatment
• What are the consequences?
• Disease issues
• Iatrogenic issues
• Summary and Conclusions

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Did God do it, or was it the Dr?

• Insulin deficiency/diabetes
• Bone disease
• Liver disease
• Urogenital problems

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CF Insulinopaenia with Normal OGTT

• Four CF patients, age 15-23 yrs
• Normal OGTT, HbA1c
• All had abnormal random blood glucose
• Trial of 6-12 units/insulin/day

Arch Dis Child 2002 87 430-1
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CF-related Glucose Intolerance Mechanisms

• N18 OGTT, n14 ivGTT, age 9-15 years
• N4 (20) impaired glucose tolerance
• N9 (65) had impaired insulin secretion
• No correlation with nutritional status, Shwachman
  score or lung function
• Clin Endocrinol 2002 56 383-9
• See also Diabet Med 2002 19 221-6

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CF Insulopaenia Prevalence

• 335 CF patients 9 diabetic (2.7)
• OGTT performed in 94, age 10-18, normal fasting
  glucose
• 16/94 (17) impaired glucose tolerance
• 4/94 (4.3) CFRD without fasting hyperglycaemia
• Impaired GT only with PI, severe mutations
• J Pediatr 2003 142 128-32

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CF Insulopaenia Consequences

• CFRD is an adverse prognostic feature
• Pediatr Pulmonol 2001 32 343-50
• Pediatr Pulmonol 2002 33 483-91
• Clinical deterioration may precede CFRD by 2-4
  years
• Eur J Pediatr 1992 151 684-7
• BlueJ 2000 162 891-5

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CF, Sugar and Insulin Conclusions

• Insulinopaenia not peripheral insulin resistance
  is the problem insulin has important anabolic
  functions
• Insulinopaenia is common suspect in PI, severe
  mutations
• Look for evidence of insulinopaenia in those with
  decline in nutrition or PFTs
• Do not be deceived by a normal OGTT
• The treatment of insulin deficiency/CFRD is
  insulin, not oral hypoglycaemics

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Dem Bones, Dem Bones..Dem Dry Bones

• One third of adults have osteopaenia or a
  pathological fracture
• Osteopaenia at best makes transplant more
  problematic

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CF Bone Disease Risk Factors

• Vit D, Vit K, Calcium malabsorption
• Systemic inflammatory response
• Lack of exercise (pathological, physiological)
• Delayed puberty, hypogonadism
• Inhaled and oral steroid therapy

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CF Bone Histomorphometry

• N20 CF adults
• Iliac crest bone biopsies after double
  tetracycline labelling (n19)
• Results
• Low cancellous bone volume, due to low bone
  formation at tissue and cellular level

BlueJ 2002 166 1470-4
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CF
CF
Normal
Normal
Normal and CF Bone biopsies
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CF Change in BMD

• Subjects 114 CF adults and children, bone
  densitometry
• Results
• Age lt 24, decrease instead of increase
• Age gt 24, decrease instead of stability

Results (n114 adults)


significant decline in BMD, plt0.05
Thorax 2002 57 719-23
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Milk and Bones Normal Adolescent Girls

• Design 18 month, open randomised trial in 82
  girls
• Subjects extra pint of milk controls, normal
  diet
• Outcome incl. BMD, bone mineral content
• BMJ 1997 315 1255-60
• Follow-up changes still present 3.5 years later
• Lancet 2001 358 1208-12

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Pathology of CF liver disease

• Mucus plugs cirrhosis
• CFTR is expressed in apical membrane of
  cholangiocytes
• CFTR controls fluid and electrolytes in bile
• Secondary inflammation (cytokines and Oxygen
  radicals)
• Modifier genes

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EpidemiologyRisk Factors

• Meconium ileus Odds Ratio 5.5 (3-11)
• Male sex Odds Ratio 2.5 (1.3-4.9)
• Severe mutations Odds Ratio 2.4 (1.2-4.8)

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EpidemiologyIncidence and prevalence

• 177 patients followed for median 14yrs
• CF Liver Disease defined as 2 of the following
• Hepatomegaly
• Abnormal liver enzymes
• USS abnormalities (excluding fatty liver)
• Cirrhosis defined on ultrasound scan

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Outcomes

• 41 with no liver disease had abnormal liver
  enzymes
• Those with CF Liver Disease wide range of
  abnormal enzymes (14 normal)
• 48/177 developed CF Liver Disease. Alllt20yrs
• 17 cirrhosis, 13 portal hypertension
• 1 decompensation, 1 transplant
• No overall effect on survival

Colombo et al 2002
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Clinical features

• Neonatal jaundice (not related to later
  cirrhosis)
• Rarely a presenting feature (1.5, USA)
• Usually diagnosed due to abnormal enzymes,
  palpable liver and liver ultrasonography
• Portal hypertension
• Acute decompensation of cirrhosis (jaundice,
  ascites)
• Biliary strictures (?)

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Regular assessment

• Abdominal exam ?hepatosplenomegaly - every visit
• Liver enzymes- annually
• Ultrasound of abdomen- 2-3 yearly
• Magnetic Resonance Imaging (MRI) cholangiography
  (specialist hepatologists)

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Portal Hypertension Oesophageal Varices

• No specific data for CF
• Varices develop in almost all cirrhotics
• Cause of death in 1/3 of cirrhosis
• First bleed 20 mortality
• Who to screen?

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Screening for varices

• Who? splenomegaly, low platelet count, spiders,
  all predictive but screen all with cirrhosis
• When?
• No varices every 3 years
• Small varices every 2 years
• Medium treat and assess every 6-12 months

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Treatment for oesophageal varices (Drugs)

• Beta-blockers reduce incidence from 25 to 15
  (40 Relative Risk reduction)
• Isosorbide Mononitrate no effect
• Beta-blockers Isosorbide Mononitrate ??
• Beta-blockers contraindicated in CF?

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Treatment for primary OVs(Interventional)

• Sclerotherpy
• Band ligation
• First line therapy
• 20 reduction in first bleed
• 16 reduction in mortality
• More effective than Beta-blocker

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• Options for long term management
• Repeated endoscopic treatment
• Long term Beta- blockers
• Surgical shunt or Transjugular intrahepatic shunt
• Liver transplantation (not often best option for
  varices)

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Liver Transplantation

• Single organ transplant
• Portal hypertension ( varices)
• Mean age 15yr
• 4/12 died within 4 months
• Survivors improved lung function
• Triple transplant (heart, lung, liver)
• 1/5 survived

Milkiewicz 2002
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Obstructive Azoospermia

• 99 of men with cystic
  fibrosis
• 1-2 of healthy men with infertility
• Most men with obstructive azoospermia carry CFTR
  mutations on one or two alleles

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Other urogenital issues

• Stress incontinence
• Male and female
• Adults and children
• During physiotherapy
• During sexual intercourse
• Candidasis
• The problems of pregnancy

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Did God do it, or was it the Dr?

• Antibiotic allergies
• Renal disease
• New gram-negative organisms

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Antibiotic Allergy The Danish Experience

• 2793 iv courses to 121 patients
• 75 allergic reactions (62 patients, 4.5 courses)

Cb
Azt
Cfs
Rev Infect Dis 1991 13 Suppl 7 S608-11
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Other Experience

• 19 CF adults with 62 antibiotic allergies
• Respirology 2003 8 359-64
• 18/53 children and adolescents allergic
• J Pediatr Child Health 1998 34 325-9

• 26/90 CF patients, penicillins gt cephalosporins
• Chest 1994 106 1124-8

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Emerging Organisms?

• 12 CF centres, 1419 patients
• Nutrition and lung function same as controls
• Variable problem (3-38)

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Emerging Organisms?

• Adults (19.2) gt children (10.5)
• 92 had received antibiotics (53 of 3497 in
  German Registry)

J Cyst Fibr 2005 4 41-8
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Risk Factors for S. Maltophilia Acquisition
Odds Ratio 95 CI
Number of IV courses Y-1
1-2 1.7 0.6-5.1
gt2 6.8 1.7-26.8
A fumigatus 5.9 2.0-17.8
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Side-Effects of Antibiotics

• 80 adult CF patients, 24.2 yrs (range 16-56)
• Chronic Ps aer infection (gt3 ve sputum in 6/12)
• FEV1 63 (16-117)

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Nephrotoxicity of Aminoglycosides
(Nos.)

• Inverse relation with intravenous aminoglycoside
  courses
• Worse if intravenous aminoglycoside plus colistin
• Not worse with intravenous colistin plus others

gt80
lt60
ml/min/1.73m2
Pediatr Pulmonol 2005 39 15-30
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Note lifetime potential of aminoglycoside
exposure!
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Nebulized Aminoglycosides?

• 52 CF children (11.5 (SD) 5.7 yrs)
• Current Gent (n20) vs. prev. treated (n9) vs.
  never treated (n23)
• Urinary NAG (renal proximal tubular marker)
• Arch Dis Child 1998 78 540-3

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There Is No Such Thing As A Free Lunch!

• Antibiotics have brought great benefits, BUT
  ALSO
• Increased allergic reactions
• Emerging Gram Negative and others
• Subtle Side-effects
• RISKS AND BENEFITS MUST BE WEIGHED FOR EACH
  INDIVIDUAL!

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CF Multisystem, Adult Disease

• How Has this come about?
• Late diagnosis of mild phenotypes
• Effective modern treatment
• What are the consequences?
• Disease issues
• Iatrogenic issues
• Summary and Conclusions

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What does this mean?

• Be alert to the late diagnosis
• Usually pancreatic sufficient
• Non-GI presentation
• Ensure excellent conventional therapy
• Oral, nebulized, intravenous antibiotics
• Nutritional support

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What does this mean?

• Be alert to complications (new and old)
• Disease-associated and iatrogenic
• Use them to inform paediatric practice
• Bone preservation
• Detect insulin deficiency
• Count the long-term cost of treatments

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