INVESTIGATIONS & TREATMENT

PRESENTER :DR GOWRI SANKAR P S

MODERATORS:
DR CH BUJJAIAH ,MD ,ASSOCIATE PROFESSOR
DR B PRASANTHI ,MD,ASSISTANT PROFESSOR
 CYSTIC FIBROSIS
INVESTIGATIONS
AND MANAGEMENT
INVESTIGATIONS & TREATMENT
PRESENTER :DR GOWRI SANKAR P S
MODERATORS:
DR CH BUJJAIAH ,MD ,ASSOCIATE PROFESSOR
DR B PRASANTHI ,MD,ASSISTANT PROFESSOR
The diagnosis of cystic fibrosis is based on compatible clinical findings, with biochemical
or genetic confirmation

THE SWEAT CHLORIDE TEST is the mainstay of laboratory confirmation

The sweat chloride test remains the criterion standard for the diagnosis of cystic fibrosis.
Most diagnostic laboratories screen for 20-30% of the most common mutations, identifying
approximately 90% of chromosomes affected in CF. The remaining 10% of affected
chromosomes comprise more tha than 400 different pathologic mutations of CFTR.

A sweat chloride value greater than 60 mEq/L distinguishes CF from other forms of chronic
pulmonary disease
However, normal sweat chloride concentrations may be observed in approximately 1% of
patients with CF, who have unusual genotypes (ie, 3849+10kb CT or poly T defects).
PROCEDURE

The test is performed by collecting sweat with pilocarpine iontophoresis on 2 or more

occasions and by chemically determining the chloride concentration.

Conditions other than CF that are associated with elevated sweat electrolyte concentrations
include adrenal insufficiency, anorexia nervosa, celiac disease, malnutrition,
hypothyroidism, and congenital metabolic diseases

The incidence of erroneous sweat test results is probably in the range of 10-15%, and most
errors represent false-positive results

Most errors are caused by the use of unreliable methodology, inadequate sweat collection,
technical mistakes, and misinterpretation of results

False-negative results can be seen in hypoproteinemic edema and with the concurrent
administration of steroids.
Nasal potential-difference measurements
Abnormalities in epithelial chloride secretions can be demonstrated in most patients with CF
by evaluating the nasal transepithelial potential difference in the basal state. This test is
performed after nasal perfusion with amiloride and after nasal perfusion with a chloride-free
solution.

Three features distinguish cystic fibrosis:

•Increased basal potential difference, which reflects enhanced Na + transport across a relatively
chloride-impermeable barrier.

•Greater inhibition of potential difference after nasal perfusion with the Na + channel inhibitor
amiloride, which reflects inhibition of accelerated Na + transport

•Little or no change in potential difference in response to perfusion of the nasal epithelial

surface with a chloride-free solution in conjunction with isoproterenol, which reflects an
absence of CFTR-mediated chloride secretion.
An increased (ie, more negative) basal nasal potential difference is strong evidence of CF. The
presence of nasal polyps or inflamed mucosa may yield a false-negative result. The presence
of a large response to chloride-free perfusion is strong evidence against CF. The test should be
performed only by experienced CF centers because standardization of the location of
measurement is critical.
Immunoreactive trypsin test

Infants with CF have elevated blood levels of immunoreactive

trypsin (IRT), which can be quantitated by means of
radioimmunoassay or enzyme-linked immunoassay.

A negative result is not informative in patients older than 8

weeks. The test may be particularly useful for small or
malnourished infants in whom the sweat chloride test cannot be
performed successfully.

Overall, false-positive and false-negative rates are relatively

high.
 .

Stool fecal fat and pancreatic-enzyme secretion tests

Stool fecal fat and pancreatic-enzyme secretion can be

measured by collecting duodenal fluids after simulation with
secretin and pancreatozymin.

Decreased levels of pancreatic enzymes or elevated stool fat

are expressed as the percentage of ingested fat in a 72-hour
stool collection and can be indicative of CF, respectively
Molecular diagnostic tests

The molecular diagnosis is usually based on a direct mutation

analysis.

A variety of techniques are used to identify specific known

mutations in the nuclear type sequence of the CFTR gene
RADIOLOGICAL EVALUATION

• Medical imaging provides an invaluable service for the diagnosis and treatment of
cystic fibrosis.
• Each modality is valuable in detecting different symptoms that can arise due to cystic
fibrosis.
• Possible connections between abdominal and pulmonary pathologies have increased
the likelihood of catching cystic fibrosis using multiple imaging modalities together.
RADIOLOGICAL EVALUATION

• Prenatal diagnosis
• Post natal diagnosis
• Pulmonary manifestation
• Extra pulmonary manifestation
PRE-NATAL DIAGNOSIS

• Pre-natal diagnosis of CF and post-natal complications is well documented

• Fetuses with CF have been associated with hyperechogenic fetal bowel
detected by ultrasound during the second and third trimesters of
pregnancy.
• Bowel is considered hyperechogenic if its echogenicity (brightness) is equal
to or greater than that of the adjacent iliac bone
PULMONARY MANIFESTATIONS
Radiography

Chest x-rays are insensitive to the early changes of cystic fibrosis, with changes
seen on HRCT in 65% of patients with CF and normal CXR. Later changes
include:
- Hyperinflation
- Bronchiectasis
- Lobar collapse
- Pulmonary arterial enlargement due to pulmonary arterial hypertension is
seen in patients with long standing disease
Brasfield scoring system

Is a scoring system for cystic fibrosis. It is based on plain film radiographic findings and has
been reported to have a good correlation with pulmonary function

Overall score: 25-total de merit points (the lower the overall score, the worse the Sdisease
severity) Minimum possible score: 3
HRCT chest

As the criterion standard as a diagnostic tool for bronchiectasis, bronchography has

been almost completely replaced by HRCT.

• HRCT has become indispensable in the monitoring of CF patients, and is used to

guide therapy and assess response to treatment, as it not only correlates with lung
function.
• Typically scans are repeated every 6 to 18 months depending on institution and
clinical course.
• Mucous plugging is of particular importance as it is thought to precede infective
exacerbations and thus identification of such plugging may be used to trigger
changes in therapy.
HRCT CHEST findings
NOSE AND SINUSES

• The upper airways are very frequently affected in CF, with over 75% of
patients reporting some kind of sinus or nasal symptom such as nasal or
sinus obstruction, nasal discharge, post-nasal drip and facial pain
• Imaging findings includes small hypoplasic sinuses, thickened nasal
turbinates and thickened mucosa of the sinuses.
• Chronic inflammation and thickening of the mucosa of the nasal cavities
and sinuses result in formation of inflammatory polyps and the
accumulation of mucus in obstructed sinuses
EXTRA PULMONARY MANIFESTATION

• Abdominal manifestations in cystic fibrosis are common, varied and

nearly all organ systems can be affected. Only 39% of patients with
cystic fibrosis (CF) have pulmonary symptoms as their sole complaint.
This include:
• Pancreatic manifestations
• Hepatobiliary manifestations
• Gastrointestinal manifestations
• Renal manifestations
• Musculoskeletal manifestations
PANCREATIC MANIFESTATIONS

• Autolysis of the pancreas due to viscous pancreatic enzymes and obstructed

pancreatic ducts is known to start during intra-uterine life
• This leads to fibrosis, atrophy and replacement of the pancreas by fat which
clinically results in exocrine pancreatic insufficiency and malabsorption in up to
90% of patients.
• Pancreatic cysts are a relatively common finding in CF and can vary in size and
number. Rarely, cysts can replace the entire pancreas in a condition called
pancreatic cystosis, which can cause pain through mass effect
HEPATOBILIARY MANIFESTATIONS

• Hepatobiliary manifestations are common in CF and include fatty

infiltration of the liver (steatosis), focal biliary cirrhosis with portal
hypertension, microgallbladder and gallstones.
• Patients are more frequently asymptomatic, but liver disease is the
second most common cause of death in CF.
• Splenomegaly as a result of portal hypertension can be seen as
massive enlargement of the spleen causing pain, dyspnea and signs of
hypersplenism and sometimes complicated with splenic infarcts or
subcapsular haematomas.
GASTROINTESTINAL MANIFESTATIONS

• Meconium ileus:
- Bowel blockage of the newborn or meconium ileus is seen in 15-20% of
neonates with CF and 25% of infants with meconium ileus prove to have CF
- Classically, above the obstruction the bowel is greatly distended with fluid
content, while below this level, the distal ileum and colon are collapsed. Soon after
birth, usually in 24 to 48 hours, the newborn will present with abdominal
distension and vomiting.

• Distal intestinal obstructive syndrome:

- DIOS is the equivalent of meconium ileus in adults.
- It affects up to 15% of CF patients as a result of thickened intraluminal
secretions, undigested food secondary to exocrine pancreatic insufficiency and
impaired bowel motility
- Abdominal radiograph and CT show dilated small bowel loops with fluid levels
and faecal material within the small bowel ("small bowel faeces").
GASTROINTESTINAL MANIFESTATIONS

• Intussusception:
- Intussusception is more common in CFpatients than in the general
population and is seen in 1% of paediatric patients. It is rare in adulthood and
comprises 5% of all intussusceptions and 1% of bowel obstructions.
- Imaging reveals a bowel-within-bowel configuration which is
pathognomonic of the condition.

• Fibrosing colonopathy:
- In association with children prescribed high strength pancreatic enzyme
supplements.
- Imaging has a limited role demonstrating non-specific large bowel wall
thickening and final diagnosis is usually obtained with histology, which depicts
submucosal fibrosis
RENAL MANIFESTATION

• Nephrolithiasis:
- Another important differential diagnosis of acute abdominal pain as there is a
reported increased frequency of renal stone disease in CF in comparison to the
general population.
- Initial assessment can be made with a CT of the kidneys, ureters and bladder
(CT KUB) to confirm the diagnosis or with an ultrasound scan if obstruction and
hydronephrosis is suspected in a patient with know nephrolithiasis.
MUSCULOSKELETAL MANIFESTATIONS

• Hypertrophic pulmonary osteoarthropathy:

- This condition consists of a triad of clubbing, symmetric arthritis and
periosteal new bone formation
- Firstly, associated with brochogenic carcinoma, it is also recognised in
bronchiectasis, chronic lung inflammation and infection and CF
CASES
 CASE – 1
A 24-year-old man with right sided pleuritic chest pain presents to the
emergency department.

Chest radiograph shows increased lung volumes and diffuse interstitial opacities emanating from the
hila; many of them are parallel, indicative of bronchiectasis (worse in the upper lungs). Branching
tubular densities in the right upper lobe represent mucus impaction in dilated bronchi. A small right
pneumothorax is also present.
CT findings include bronchial wall thickening, tubular and varicoid bronchiectasis signet-
ring, mucoid-impacted bronchioles causing tree-in-bud, and mosaic attenuation due to
air-trappina
CASE – 2
A 26-year-old male chronically ill patient with nausea, vomiting and
dehydration

Ct Images of the chest

in lung windows -
demonstrated
profound, diffuse, cystic
dilatation of the airway.
CT images of upper
abdomen in soft tissue
windows –
demonstrate a nodular,
cirrhotic appearing liver,
splenomegaly and
complete fatty
replacement of the
pancreases
Pulmonary MRI can provide high-resolution images that are sensitive to early CF
and specific to inflammation in CF lung disease.

Contrast perfusion MRI can be used to identify changes in pulmonary and bronchial
circulation that routinely occur in CF lung disease.

Hyperpolarized-gas MRI is becoming more widespread and has been shown to

have high sensitivity to early airway obstruction in CF via ventilation MRI. In the
depiction of bronchial wall thickening, bronchial dilatation, and mucous plugging, the
resolution of MRI does not compare favorably with that of CT. [51]

The usefulness of Lung Scintigraphy is limited. The main problem is the correct
clinical use of a test with such a high sensitivity and a high percentage of false-
positive results
Decreased bone density is common among patients with CF;
this finding usually reflects a lack of control of the illness, and
it often remains unfound with the usual investigations.

If possible, dual x-ray absorptiometry should be part of the

investigations in these patients
Bronchial arteriography has a role in detecting the bleeding site.
It is also useful in subsequent embolotherapy in patients with
advanced CF and major or persistent and significant hemoptysis

Although hemoptysis is correlated with bronchial artery

hypertrophy and a bronchopulmonary anastomosis within the
bronchial walls, the role of prophylactic angiography for further
interventions has not been studied.

Angiography is invasive and usually performed in the setting of

acute significant hemoptysis
Diagnosis… Criteria:

1. *Clinical symptoms consistent with CF in at least

one organ system

2. Evidence of CFTR dysfunction via

• *Elevated sweat chloride >60mmol/l (two tests)
• Disease causing CFTR by genetic testing
• Genetic mapping is not mandatory for diagnosis, but
can help to confirm diagnosis and may assist in
therapeutic options Cystic Fibrosis
Treatments…Two Catagories

 Symptomatic Treatments
Remains primary form/category of therapy at this time  Has
significantly increased life expectancy; primarily through antimicrobials
(oral, IV, inhaled)  Rigorous daily oral, inhaled & airway clearance
regimens
 Causative Treatments
 Restores partial/full CFTR production & function
 Depending on gene mutation(s)
 Gene Therapy
 Kalydeco® (Ivacaftor)
 Orkambi® (Ivacaftor + lumicaftor)
Symptomatic Treatment…
P.aeruginosa is considered a major pathogen.
S. aureus and H. influenzae also significant.
Initial colonization period with non-mucoid strains of P.aeruginosa are followed by
chronic infection with mucoid strains.
Mucoid strains generally cannot be eradicated likely due to poor penetration of
antibiotics into anaerobic sputum plugs and into mucoid layer (biofilms)
Rapid mutator strains of bacteria form with increased resistance

Inhaled therapy with anti-pseudomonas agents have had positive clinical impact.
Sputum Culture/ Sensitivities guide but do not dictate choice:

Tobramycin neb suspension: 300mg/5mls or 300mg/4mls inhaled BID x 28 days on/

28 days off then repeat cycle  TOBI®
Podhaler: 112mg (28mg/cap) inhaled BID
Colistimethate: 75mg to 150mg inhaled BID x 28 days on/28 days off then repeat
cycle. Reconstitution required
Aztreonam: 75mg inhaled three times daily x 28 days on/ 28 days off then repeat
cycle
Daily Antibiotic therapy

Chronic azithromycin:

250mg po once daily or 500mg po 3 x per week

Standard anti-bacterial properties
Indirect anti-inflammatory properties
Managing CF related bronchiectasis- airway inflammation secondary to
persistent infection
Sputum culture x 3 prior to initiation to r/o NTM
Mucolytics (Decreases sputum viscosity, improves lung function,
decreases exacerbations):

Deoxyriboneuclease (Dnase or Dornase®): inhale 2.5mg/2.5mls via

nebulizer once daily.

Hypertonic Saline (HyperSal®) 3% or 7%: inhale 4mls via nebulizer once

to twice daily (albuterol use prior).

• Clinically, patients encouraged to use during airway clearance with

VEST® or other chest percussion devices

• SABA (MDI and/or nebulized solution):

The direct intracavitary percutaneous instillation of
glycerin and amphotericin B with CT guidance has shown
promise in the treatment of symptomatic patients with
mycetoma (aspergilloma) as a complication of a
preexisting cavity with extensive bronchiectasis
Nutrition

• Fat, protein and fat-soluble vitamin absorption is reduced or absent in

pancreatic insufficiency
• Oral Enzyme Replacement Therapy is necessary to control steatorrhea
and encourage nutritional health
• Nutritional status is closely correlated with lung function
• BMI & growth rate is closely monitored
• Weight loss is one sign of CF exacerbation
• Inter-patient variability/preference exists among enzyme replacement
products
Nutrition

• Oral enzyme replacement therapy dosed using units of lipase/kg/meal: Maximum:

2,500 units lipase/kg/meal or snack
Each capsule contains: lipase, amylase, protease
Capsules can be opened and contents placed in or on food Powder also exists for
use in formula

• Total daily dose (capsules/powder) is titrated by patient/caregiver based on

content of fat or protein in meals and snacks

• Titration also based on bowel movements (number per day, and fat content) •
Creon®, Zenpep®, Pancreaze®, Pertzye®, Viokase®, generics

• Antacids (PPI or H2-blockers) often prescribed for daily use

• Fat soluble vitamin replacement is often required (ABDEK)

• Traditional OTC multivitamins are generally not interchangeable for CF vitamin
on a oneto-one basis.
• • Can use separate A,D,E,K if needed
• • Monitor serum vitamin levels; bone density
OGTT to monitor for CFRD
• Once annually to every other year
• Insulin is the only appropriate therapy in CFRD
• Typically, Glargine used once to twice daily
• Lispro used per sliding scale and/or per gram of carbohydrate intake •
Diabetes clinic referral: Diabetes Education helpful
• Nutritional consultation varies widely from nonCFRD: high
calorie/high protein/high fat diets
Symptomatic Treatment… 

Oral prednisone (1 to 2 mg/kg every other day): improved lung

function & reduced frequency of exacerbation x 2 years only. Generally
used w/ antimicrobial therapies.
Risks may outweigh benefits

Inhaled Corticosteroids +/- Long Acting Beta 2Agonists: Insufficient

evidence to establish whether ICS +/- LABA is beneficial in CF
maintenance. CFF guidelines discourage use w/o clear asthma
diagnosis

LABA alone: may be used in patients without associated asthma

diagnosis Growth rate can be affected in pediatric population Use of
ICS in CF patients with asthma co-morbidity is acceptabl e
New & Future…
Kalydeco® (Ivacaftor):
FDA approved, 2012 for CF patients with G551D  150mg orally BID
February 21, 2014 the FDA approved the expanded use for G178R,
S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D
mutations
Potentiates function of chloride-ion channel

Counseling Points:
Take with fat-containing foods
Monitor Liver Enzymes
Several DDI: Decrease dose with Inhibitors of CYP3A (ie,
clarithromycin or fluconazole)
Do not use with inducers of CYP3A (ie, rifampin)
May require less enzyme replacement therapy
Orkambi®: (Lumicaftor + Ivacaftor)
FDA approved July 1st, 2015
Both entities in each tablet (200mg/125mg/tab)
Two tablets (400mg/250mg) orally BID
CF patients with 2 copies of Δ F508 only
Corrects & potentiates function of chloride-ion channel

Counseling points: -
Take with fat-containing foods (nuts, eggs, avacodo)
-Monitor Liver Enzymes
- Baseline and periodic eye exam (pediatric recommendation)
-Several DDI: Decrease dose with Inhibitors of CYP3A (ie, clarithromycin or
fluconazole)
-Do not use with inducers of CYP4503A (ie, rifampin) - May decrease
efficacy of oral contraceptives; recommend 2 form s
Repairing the defective Δ F508 protein is particularly
challenging. In this mutation, a series of problems
prevents the protein from reaching the surface of the
cell.

Lumacaftor exposure moves the Δ F508 CFTR protein

to the cell surface where Ivacaftor can improve its
function helping to increase the flow of chloride and
ultimately water in and out of the cell
VX661 + Kalydeco

VX-661 is a “corrector”, designed to work with Ivacaftor to

move defective CFTR protein to the proper place in the
airway cell membrane and improve its function as a
chloride channel

In Phase 3 trials for CF patients with two copies of delF508

(most common genotype)
Ataluren

Non-sense mutation(s)

In Phase 3 trial A novel, small

molecule compound that
promotes the read-through of
premature truncation codons in
the CFTR mRNA
Common Daily Regimen*:
Acetaminophen 500mg/tab: 1-2 tablets q6hr prn
Albuterol MDI: 2 puffs q 4 to 6 hours prn
Albuterol 2.5mg/3ml solution: Inhale 3mls by neb q 4 to 6 hours as needed (when not
using MDI)
Azithromycin 250mg/tab: 1 tablet daily
Aztreonam 75mg/ml: Inhale 75mg by neb TID x 28 days on, then 28 days off, then repeat
cycle (alternate cycles with TOBI)
Fluticasone Propionate NS: 50mcg in EN BID
Citalopram 20mg/tab: 1 tab daily Cholecalciferol 5000 i.u/tab: 1 tablet daily
Dornase Alpha 1mg/ml: Inhale 2.5mg/2.5mls by neb daily
Insulin Glargine: 10 units SC once daily;
Insulin Lispro: 2 units SC per SS
Lactobacillus: 2 capsules BID
CF Multivitamin (AquaADEKs): 2 capsules daily (with or without additional VitD)
Mupirocin 2% ointment: Apply to nares BID prn
Omeprazole 20mg/capsule: 1 capsule daily

Oxycodone 5mg/tab: 1 to 3 tablets every 6 hours as needed for pain

Creon 24,000: 4 to 5 capsules with meals; 2 to 3 capsules with snacks

Sinucleanse Squeeze Nasal Rinse: Mix and rinse sinuses once daily

Tobramycin: 300mg/5ml inhalation suspension: 300mg/5mls by neb BID x 28 days on/

28 days off; then repeat cycle (alternate with Aztreonam)

HyperSal 7% inhalation solution: Inhale 4 mls by neb once to twice daily with VEST

Zolpidem 5mg/tablet: 1 tablet at HS prn +/- Kalydeco or Orkambi BID *

Doesn’t include time to use devices such as VEST twice daily. Patients will not use two

inhaled antibiotics in the same month

Managing CF Exacerbations… Treatment:
• Continue most daily medications
• Consider Inhaled antibiotic therapy initiation or change in dosing • Consider oral
prednisone burst (10mg/day x ~10 days)
• Add: At-home or In-Patient oral or IV therapy x 14 days (dual IV antibiotic regimens are
common; inhaled antibiotics discontinued most often)
• Sputum Culture/Sensitivity to guide choice; does not dictate choice
• May require PICC line or can consider placing Hickman Catheter • Often 1 anti-
pseudomonas agent (Tobramycin) and 2nd broad spectrum agent:
• Tobramycin 5-10mg/kg/dose (q 12 hours versus q 24 hours) • Ciprofloxacin: 600mg IV
Q12 hours
• Piperacillin/Tazobactam: 4.5 Gram IV Q 6 hours • Cefepime: 1 Gram IV Q 8 hours or Q
12 hours
• Meropenem: 2 Gram IV Q 8 hours
• Monitoring of Peak/Trough levels of Tobramycin necessary, SCr, HCG
• Increase airway clearance frequency
CF Exacerbations… Special Populations:
• Pregnant women
• Patients with %FEV1 < 30 %predicted
• + MRSA patients
• NTM (non-tubercular mycobacterium) infections
• MDR pathogens in sputum
• Renal function compromise
• Patients with multiple drug allergies and/or
intolerances
• Line-related DVT and anticoagulation
Transplantation in CF…

Considered when %FEV1 < 30 % predicted

Typically “Double-Lung” versus “Single-Lung”

Patient still has “CF”  Several daily medications remain post-op

Several new medications begin post-op

Average life expectancy post-op: ~5 years

Vaccinate completely prior to transplantation