Bucharest 2015

TITANIC 11april 1912

Adult cystic fibrosis care

Complex

Challenging

Rewarding

Exciting times in CF

Burgel et al. Eur Respir J. 2015 Mar 18. pii: ERJ-01963-2014. (Epub ahead of print)

PREVALENCE

CUH POPULATION

Plant et al. Lancet Resp Med 2013

Born 1990 Predicted Median survival > 40 years Elborn et al. Thorax 1991

Born 2000 Predicted Median survival > 50 years Dodge et al. ERJ 2007

Today it is the expectation that a child born with CF

will survive to become an adult….

Cuh Ireland

+ Fleming C et al. 2014

22

73

37

18

4 3

0

10

20

30

40

50

60

70

80

16-19 20-29 30-39 40-49 50-59 70-80NO Column2

46%

23%

11%

3% 2%

14%

Life is a transition Baby

Toddler

Playschool

Primary

Secondary

College

Leaving home

Work

Marriage

Health issues

Aging

Retirement

death

Kidney disease

cancers

Mental health

Plant et al. Lancet Resp Med 2013 in press

Massive Hemoptosis- 1.8% of all adults

Increases with age Increases with worse

Lung function

Flume, P. A. et al. Chest 2005;128:729-738

Massive haemoptysis

Conservative

Stop nebulized medication

Intravenous antibiotics

Transexamic acid

Vitamin k

Bronchial artery embolization

Poor prognosis Prognosis worsens

With poorer Lung function

Pneumothorax - 1.4% of all adults

Flume, P. A. et al. Chest 2005;128:720-728

Treatment lung disease

physiotherapy

Autogenic drainage Devices used to aid physio

Intravenous antibiotics (inpatient or

home IV)

CEFTAZADIME AND TOBRAMYCIN

MEROPENAM CEFTAZADIME AND TOBRAMICIN

MEROPENAM CEFTAZADIME TOBRAMYCIN

CASPOFUNGIN

MANY MORE COMBINATIONS

Type of venous access

Cannula Midline

Portacath inserted when

difficulty inserting midline

Pic line

Ear nose throat

pancreatitis

GERD, Oesophagitis,

Barret’s Oesophagus

Gastrointestinal

Absence of Oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria. Lancet

1998; 352: 1026-9.

43 paediatric CF patients; 21 healthy volunteers (<10yrs)

Stool culture and DNA

71% (15) of healthy volunteers colonised

16% (1+6) of CF patients colonised

C. Difficile

Adults: n=37 CF / n=12 Resp. Controls / n=28 Controls

32% CF C.Diff vs. 17% Resp. Controls vs. 3.6% controls Peach et al. J Clin Path 1986

Helicobacter pylori and Clostridium difficile in cystic fibrosis patients.

Dig Dis Sci. 2006 Dec;51(12):2274-9.

Prevalence of H. pylori antigen:

16.6% (5/30) CF patients vs.30% (9/30) in controls.

H. Pylori

CF GUT Micriobiota

Prevalence of C.Difficile in CUH population

Screened for C. difficile (culture-based)

49% (26/53) positive for C. difficile

vs. 2% (2/100) of healthy controls

Highest reported prevalence of C. difficile in CF to date examining the role of Clostridium difficile in the gut

First study to characterise Clostridium difficile ribotypes and antibiotic sensitivities in people with Cystic Fibrosis.

The study revealed a high prevalence of Clostridium difficile, including many hyper-virulent strains, in the gut of adults with Cystic Fibrosis without clinical evidence of Clostridium difficile-associated disease.

The findings highlight the potential role of patients with Cystic Fibrosis as pathogen reservoirs for Clostridium difficile.

Harrison MJ et al ECFC 2013

CFRD

Prospective study UK CFR data 1996-2005 n=3275

CFRD incidence is high and increases with age

Adler AL, Shine BSF et al. Genetic Determinants and Epidemiology of Cystic fibrosis-related diabetes. Diabetes Care.

2008;31:1789-1794.

CF Related Diabetes

All adult patients should have an annual glucose tolerance

test

If impaired it should be repeated in 6months

If abnormal glucose monitoring should start immediately

Referral to diabetic clinic

Treating cystic fibrosis related diabetes

Insulin is the only recommend treatment

People with CFRD with glycaemic control on target

Improved BMI

Improved pulmonary function

Decreased pulmonary exacerbation rates

Moran A, Brunzell C, Cohen RC; CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010.;33(12):2697-708. Moran A, Pekow P, Grover P; Cystic Fibrosis Related Diabetes Therapy Study Group Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care. 2009; 32(10):1783-8. Mohan K et al. Long-term effect of insulin treatment in cystic fibrosis-related diabetes Respiration. 2008;76(2):181-6

Micro-vascular disease with CFRD..

1990-2005

775 aged >6 years

No subjects without fasting hyperglycemia (FH)

had retinopathy or abnormal Ualb:cr

All subjects with CFRD >14years developed FH

FH ≥ 10years:

14% Microalbumin

16% Retinopathy

Microvascular Complications in Cystic Fibrosis-Related Diabetes. Schwarzenberg SJ et al. Diabetes Care 2007

Renal disease in cystic fibrosis

Acute kidney injury

Aminoglycosides

NSAID toxicity

Heat exhaustion

Nephritis

Chronic kidney disease

Nephrocalcinosis

Kidney stones

IgA nephropathy

Renal amyloidosis

Nodular glomerulosclerosisis

Treatments Nifiedine which is a calcium channel blocker, rapidly lowers

blood pressure and open up the smaller capillaries

Bosentan 62.5 and increased to 125 mgs in an effort to

improve his digital ulceration

Sildenafil-(Viagra) 20 mgs 8hrly

GTN Patches

I/V Iloprost-(Prostacycline)- aim to widen blood vessels for

a few months

Right palmar sympathectomy in December 2010. Blood

vessels were found to be highly calcified

Liver disease in CF

Bloods for Liver disease on annual review

5% of adults have cirrhosis

1-2 yearly Liver ultrasound

Referral to Liver specialist

varices –portal hypertension

Liver transplant

Distal intestinal obstruction syndrome

Severe genotype

Pancreatic insufficiency

Dehydration

Poorly controlled fat malabsorption

History of meconium ileus

History of Dios

Post organ transplant (10-20%)

CF related diabetes

Constipation

Appendicitis

Appendicular mass

Mucocele of the appendix

Intussusception

Crohn’s disease

Adhesions

Volvulus

Fibrosing colonopathy

Malignancy

Risk factors Differential diagnosis

• Risk Factors: Previous DIOS / Homozygosity for DF508

• SIR did not vary with age

• SIR higher in males versus females (8.4 vs. 46)

J Natl Cancer Inst 2013;105:122-129

344,114 patient-years

Cancers in CUH

Liver cancer

Testicular cancer

Bowel cancer-post transplant

Skin cancer-post transplant

Osteopenia - Osteoporosis Treatment- vitamin D calcium vit k -nutrition

Exercise -Bisphosphonate

Sex hormone treatment (if sex steriod

Deficiency is suspected)

Education for adults

Contraception

safe sex

female pregnancy

male –semen anyalisis

Genetic testing for partners

Options available to them

Fertility in CF Females

The majority of CF females can become pregnant naturally

Abnormally thick cervical mucus can be a problem

Ill health, malnutrition, irregular or absent periods can affect fertility and age

pregnancy

Pregnancy- Natural – IVF-PGD

When safe to get pregnant fev1 50%

or greater

Care of mother during pregnancy

Co-ordination of care with maternity

team

Dealing with complications

Helping mum to cope with new baby

Fertility in CF Males

97% of CF males have an anatomical defect – congenital bilateral absence of the Vas Deferens (CBAVD)

This causes obstructive azoospermia

These men cannot reproduce without ICSI

What is Preimplantation Genetic Diagnosis?

Selection of: • Genetically normal or carrier embryos from couples with

known inherited mutations Aim:

• To transfer an embryo that will develop into a healthy child

Couples:

• May be fertile

Diagnosis: • Specific • Undiagnosed embryos never transferred

Ethics / controversy: • Not allowed in some countries

Male adult cf f508/f508

Partner G551d/- pre-implantation

Daughter

Compliance with therapy Is long term doesn’t go away

Transplants

When to refer for assessment?

Fev1 <30% predicted

Increased hospitalisations

Increased antibiotics

Quality of life

Difficult time for patient and their family

Transplant CUH 19

0

1

2

3

4

5

6

1998 1999 2000 2003 2008 2010 2011 2012 2013 2014

17rs 16yrs

15yrs

8yrs 5yrs

4yrs

3yrs

2yrs

1yr-9mth

Mental health (coping with CF)

Alcohol abuse

Smoking cigarettes

Illegal drugs

Anxiety

Depression

Eating disorders

Characteristics End of life care

Difficulty in establishing a terminal phase

Reluctance to introduce palliative care in some instances

Active treatment continued until time of death

Possibility of lung transplant

The use of invasive and non-invasive mechanical ventilation

Cystic fibrosis survival improvement

due to many factors

Improved facilities

Multidisciplinary approach

Adult units on university sites

Research

Transplant survival

Late diagnosis

Multidisciplinary approach

Involves drawing appropriately from multiple disciplines to

redefine problems outside normal boundaries and reach solutions based on new understanding of

complex situations

Multidisciplinary team work or

collaboration is an approach designed to guide thinking

and practice in the healthcare system

As patients condition change

over time the composition of

team may change to reflect that

change

Adults centre work well when sited in university hospitals

Challenges of adult care

• Fertility clinics

• Obstetrics

• Ear nose and throat

• Endocrine/GI specialists

• Radiology

• Renal specialists

• Cancer specialists

• Rheumatology

• Pain specialists

• Psychologist and psychiatry teams

Team Staffing complement per 150 patients

Consultant 1.5

SPR 0.8

Staff grade fellow 1

Specialist nurse 3

Physiotherapist 4

Dietician1

Social worker 1

Clinical psychologist 1

Pharmacist 1

Secretary 1

Database co-ordinator 1

Worldwide Prevalence of G551D

Mutation

7.4%

4.4%

3.4%

5.6%

* Based on international registry data

Cork 23% Ireland 12%

Clinical Outcomes of Real-World Kalydeco (CORK) Study A prospective 12 month analysis addressing the impact of CFTR modulation on the Cystic Fibrosis Lung

Ronan NJ1,2, O’Callaghan, G1,2 , Mooney D3, Einarsson G3, Elborn JS3, NiChroinin M1,

Mullane D1, Murphy DM1,2, O’Connor OJ4, Shortt C1, Tunney M3, Twomey M4,

Maher MM4, Eustace JA2, Plant BJ1,2

1Cork Cystic Fibrosis Centre, Cork University Hospital, University College Cork, Cork, Ireland 2HRB Clinical Research Facility, University College Cork, Cork, Ireland.

3 CF & Airways Microbiology Research Group, Queen’s University Belfast, Belfast, United Kingdom 4Department of Radiology, Cork University Hospital, University College Cork, Cork, Ireland

ECFC 2015

Methods

0

2

4

6

8

10

12

Baseline 3 Months 6 Months 9 Months 12 Months

Mean Change in FEV1 (% predicted)

-70

-60

-50

-40

-30

-20

-10

0Basline 3 Months 6 Months 9 Months 12 Months

Mean Change in Sweat Chloride (mmol/l)

0

1

2

3

4

5

6

Baseline 3 Months 6 Months 9 Months 12 Months

Mean Change in weight (kg)

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

Basline 3 Months 6 Months 9 Months 12 Months

Mean change in BMI (kg/m2)

P < 0.01

P < 0.01

P < 0.01

P < 0.01

0

20

40

60

80

100

120

pre post

Mean change in Shuttle walk test

P< 0.01

Ronan et al. ECFC 2015

Antibiotic Requirements

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Pre Post

Mean number of IV Exacerbations per patient

76% reduction in IV

antibiotics

P = 0.003

Ronan et al. ECFC 2015

CASE PRESENTATIONS

37YR OLD MALE AF508/G551D Fev1 14% ON ACTIVE TRANSPLANT LIST

SEVERE ANXIETY

3MONTHS IN HOSPITAL- KALYDECO

HOME I/V BIPAB/OXYGEN

TRANSPLANT

30, F

Baseline FEV1 59%

Pancreatic insufficient

CFRD

Chronic rhinosinusitis

Chronic constipation/DIOS

Sputum: P. aeruginosa

20, M

Baseline FEV1 47%

Pancreatic insufficient

Nocturnal PEG feeding

Previous nasal polypectomy

Sputum: P. aeruginosa

Adherence issues

Siblings (F508del/G551D)

Ivacaftor: Drug-drug interaction

30, F

150 mg twice daily

Standard dosing

20, M

150mg twice weekly

Significant reduction

ABPA on Itraconazole

Ivacaftor: Drug-drug interactions

0

5

10

15

20

25

30

35

40

Baseline 3 Months 6 Months 9 Months

Change in FEV1 (% predicted) from baseline

84% fev1

75% fev1

GI SYMPTOMS

24, Male University student

F508/g551d

Sweat chloride: 84 mmol/L

Baseline FEV1 82% predicted

No IV AB in previous 5 years

Major issue is chronic GI symptoms

Colonic stricture at hepatic flexure 2008

Chronic constipation (MOVICOL –GASTROGRAFFIN PO)

Recurrent abdominal pain

Self imposed dietary restrictions with certain types of food

COMMENCED IVACAFTOR 2013

70

75

80

85

90

95

Baseline 3 Months 6 Months 9 Months 12 Months

FEV1 (% predicted)

0

10

20

30

40

50

60

70

80

Baseline 3 Months 6 Months 9 Months 12 Months

Weight (Kg)

0

10

20

30

40

50

60

70

80

90

Baseline 3 Months 6 Months 9 Months 12 Months

Sweat test (mmol/L)

0

5

10

15

20

25

30

Baseline 3 Months 6 Months 9 Months 12 Months

BMI (Kg/m2)

GI symptomatology

resolved

Stopped movicol

& dietary restrictions

“Too good to be true”

Ivacaftor in R117H mutations SEVERE DISEASE

56 year old lady with CF (F508del/R117H)

Baseline FEV1 of 28% predicted

High exacerbation rate requiring 8 courses (2 in-patient) of IV antibiotics in

2011 and 9 (4 in-patient) in 2012

She was assessed for lung transplant but felt not to be a suitable

candidate

Commenced on Ivacaftor through named patient compassionate programme

Ronan NJ, Fleming C,O’Callaghan G, Maher MM, Murphy DM, Plant BJ. CHEST (in press)

Ronan NJ, Fleming C,O’Callaghan G, Maher MM, Murphy DM, Plant BJ. CHEST (in press)

17 year old

G551D/G551D -FEV1 17%

FATHER RIP

PREVIOUS PNUEMOTHORAX

4-6 COURSES OF I/V YEARLY

ASSESS FOR TRANSPLANT –IVACAFTOR

Ivacaftor changing the face of cystic

fibrosis

FEV1 44%

0NE COURSE OF

I/V

HOLIDAYS

Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for

Phe508del CFTR

Claire E. Wainwright, M.B., B.S., M.D., J. Stuart Elborn, M.D., Bonnie W. Ramsey,

M.D., Gautham Marigowda, M.D., Xiaohong Huang, Ph.D., Marco Cipolli, M.D., Carla

Colombo, M.D., Jane C. Davies, M.D., Kris De Boeck, M.D., Patrick A. Flume, M.D.,

Michael W. Konstan, M.D., Susanna A. McColley, M.D., Karen McCoy, M.D., Edward F.

McKone, M.D., Anne Munck, M.D., Felix Ratjen, M.D., Steven M. Rowe, M.D.,

M.S.P.H., David Waltz, M.D., and Michael P. Boyle, M.D. for the TRAFFIC and

TRANSPORT Study Groups

N Engl J Med 2015; 373:220-231July 16, 2015DOI: 10.1056/NEJMoa1409547

Reduction in pulmonary exacerbations 30-39%

Fev1 4.3-6.7%

Results showed that ORKAMBI was of

benefit to cf patients

The future

New therapies

CFTR Modulation

Research work together

Monitor our patients closely

Prevention of complications

Adults to reach old age with less complications

We have to think outside the box

‘Living longer with Cystic

Fibrosis’

ECFS BOOK

Due Later 2015

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