`Cystic Fibrosis

Question 1

Learning outcomes

Answer 1

• Understand the Pathophysiology of Cystic Fibrosis.

* Have a basic understanding of the management of patients with Cystic Fibrosis.

Question 2

What is cystic fibrosis

Answer 2

• Cystic fibrosis (CF) is a severely life-shortening genetic disease resulting from abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel found in cells lining the lungs, intestines, pancreatic ducts, sweat glands, and reproductive organs.

Lots of mutation causes

• The most common clinical manifestations are pancreatic dysfunction, resulting in calorie malabsorption; and lung disease, resulting from a cycle of mucus retention, infection, and inflammation.

Question 3

Discuss the epidemiology of cystic fibrosis

Answer 3

• The incidence among white people is about 1/3000; the incidence is lower among people of African, Hispanic, and Asian descent.
• It is most common among people of European descent.

Question 4

Discuss the pathophysiology of cystic fibrosis

Answer 4

• Mutations in cystic fibrosis transmembrane conductance regulator CFTR result in abnormal salt transport by epithelial cells, resulting in thick, sticky secretions.
• In the pancreas, this leads to blockage of exocrine ducts, early activation of pancreatic enzymes, and eventual autodestruction of the exocrine pancreas. Therefore, most patients require supplemental pancreatic enzymes.
• In the intestine, bulky stools can lead to intestinal blockage.
• In the respiratory system, the absence of CFTR function results in mucus retention, chronic infection, and inflammation that eventuate in the destruction of lung tissue.
• Lung disease is the most common cause of morbidity and mortality.

Question 5

Discuss newborn screening for CF

Answer 5

• The Cystic Fibrosis Foundation recommends newborn screening for all infants if performed appropriately.
• It is performed by quantifying serum immunoreactive trypsinogen from a dried heel-stick blood spot.
• Newborn screening allows for early diagnosis and treatment, and provides significant clinical benefits, including improved nutrition and cognition.
• It may also decrease lung disease and admissions to hospital

Question 6

Discuss diagnosis of CF

Answer 6

• Age of onset of CF is variable. Patients with classic CF will generally present in infancy or early childhood with failure to thrive.
• Some infants and young children will present with prolonged or severe bronchiolitis or recurrent respiratory complaints.
• Undiagnosed adults with CF, who are usually pancreatic sufficient, may present with chronic or recurrent bronchitis, sinusitis, or pancreatitis.
• The introduction of newborn screening means many patients are now diagnosed immediately after birth.

Question 7

Discuss the birth history taking for suspect CF

Answer 7

• The birth history should include questions regarding the passage of meconium (because delayed passage may be a sign of the condition) and the place of birth (because many countries perform newborn CF screening).
• A positive family history should raise the level of suspicion of CF in the patient.
• The family history may reveal a distant relative who died because of a respiratory disease reminiscent of CF

Question 8

What is meconium?

Answer 8

Dark green substance that is the first faeces of an infant

Question 9

Discuss the resp. tract history in someone with CF

Answer 9

• The family should be questioned regarding respiratory rate, presence of retractions, cough, or wheeze.
• The presence of cough should prompt further questions regarding the quantity and quality of cough and sputum production.
• A wet-sounding cough, particularly with hard coughing spells, may be consistent with CF.
• Patients may present with a history of recurrent lower airways infections, either bronchitis or pneumonia, necessitating antibiotic therapy.
• Haemoptysis, such as blood-streaked sputum during a pulmonary exacerbation, is often observed.

Question 10

Discuss the GI tract history in someone with CF

Answer 10

• The patient (or more likely the patient’s parents) should be questioned regarding appetite, kinds of foods eaten on a typical day, stooling habits, including quantity and quality, and presence of gastro-oesophageal reflux.
• The presence of an insatiable appetite along with large numbers of stools or bulky, greasy stools is consistent with fat and calorie malabsorption and should raise the level of suspicion.
• A history of decreasing stool numbers over time, with or without abdominal distension or vomiting, may signal bowel obstruction, which is more common in people with CF than in those without.
• Patients may also present with recurrent pancreatitis and/or acute appendicitis.

Question 11

Discuss the physical examination of someone with CF

Answer 11

• The physical examination may be normal in a patient with CF.
• However, there are a few key findings that should raise the level of suspicion:
• The appearance of malnutrition (lack of subcutaneous fat stores, protuberant abdomen, below normal weight-for-height [in infants and young children] or BMI [in older children, adolescents, and adults]).
• Nasal polyps.
• Increased anteroposterior diameter of the chest, and crackles at auscultation.
• Digital clubbing of the hands.
• Palpation of the abdomen may reveal a stool mass (often in the RLQ), an enlarged liver, spleen, or both.
• In males, bilateral absence of the vas deferens.

Question 12

Discuss the investigations done in someone with suspected CF

Answer 12

• If suspected (i.e., patient presents with symptoms/signs or a positive family history), a sweat test (pilocarpine iontophoresis test) should be performed.
• In this test a small amount of pilocarpine is placed on the skin of the forearm to stimulate sweating.
• To absorb the Pilocarpine into the skin, the area is stimulated by a small current from a battery, for around five minutes. This may produce a tingling sensation, but it does no harm and does not hurt.
• The stimulated sweat is collected in a microcapillary tube so that its chloride content can be measured.
• It is generally considered the most conclusive test for diagnosis and has several advantages, including being painless, relatively inexpensive, providing results within a few hours, and being accurate when performed at a qualified centre.
• Sweat tests may be performed in children of any age. Some children may not produce enough sweat to give accurate results. If this occurs, the child should be retested within a week.
• For most patients, a sweat test remains the best diagnostic indicator.
• For those with a sweat test falling in the intermediate range (defined as a sweat chloride measurement of 30-59 mmol/L [30-59 mEq/L]), further investigations may be required.
• Genetic testing can help to establish the diagnosis.
• Most laboratories will perform an initial ‘screen’ for the most common cystic
fibrosis transmembrane conductance regulator (CFTR) mutations.
• If two common mutations are not found, most laboratories have an option for sequencing more of the CFTR gene or the entire CFTR gene.
• Other ancillary tests include a sinus x-ray, which may show pansinusitis, and a deep throat swab performed after a gag, which may demonstrate respiratory pathogens, although neither of these are specific tests for CF.
• A referral to a CF centre is strongly recommended for these patients

Question 13

Discuss the sweat test

Answer 13

• A negative sweat test (defined as a sweat chloride measurement of <30 mmol/L [<30 mEq/L] in all age groups) suggests that CF is unlikely. However, if questions remain, referral to a CF centre is recommended even in the presence of a negative sweat test.
• A positive sweat test (defined as a sweat chloride measurement of ≥60 mmol/L [≥60 mEq/L]) is consistent with CF and requires immediate referral to a CF centre

Question 14

Discuss management of CF

Answer 14

• CF is a genetic disease for which there is no cure.
• The most common clinical manifestations are pancreatic dysfunction, resulting in calorie malabsorption, and lung disease, resulting from a cycle of mucus retention, infection, and inflammation.
• Care is aimed at maintaining health through preventative measures, and early and aggressive treatment of complications such as poor weight gain and signs of respiratory disease.
• If signs of respiratory disease are present, early institution of assisted mucociliary clearance techniques is essential.
• For gastrointestinal disease, supplemental, exogenous pancreatic enzymes are used to support growth and nutrition.

Resp disease:
• Respiratory disease is the most common cause of morbidity and mortality. The mainstays of respiratory therapy are augmented airway clearance and use of antibiotics to treat pulmonary infections.
• Airway clearance should be performed to mobilise secretions from the airway walls into the lumen, where they can be coughed out.

• Methods include manual chest physiotherapy, active cycle of breathing, high-frequency oscillatory vest device (VEST therapy), flutter valve, or positive expiratory pressure mask.
• Non-invasive ventilation (NIV) may be a useful adjunct to other airway clearance techniques, particularly in people who have difficulty expectorating mucus. When used in addition to oxygen, it can improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate-to-severe disease.

Question 15

Discuss inhaled therapy for CF

Answer 15

• Short-acting bronchodilators (e.g., salbutamol) are generally given before airway clearance. Also used in patients who show asthma-like symptoms.
• Mucolytics, such as dornase alfa and hydrators such as hypertonic saline, are also used. Dornase alfa is a recombinant human DNase that degrades DNA from inflammatory cells in the airway.
• Inhaled antibiotics are used in patients with chronic infection with Pseudomonas aeruginosa. Chronic colonisation is associated with a more rapid decline in lung function.
• Inhaled corticosteroids are often used in patients with CF and asthma or allergic bronchopulmonary aspergillosis (ABPA) rather than as a treatment for CF lung disease.
• Anti-inflammatory agents (e.g., macrolide antibiotics, ibuprofen, corticosteroids) are used in an attempt to control inflammation in the airway.

Question 16

Discuss CFTR modulator therapies

Answer 16

• Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are small molecules that can partially restore function in mutated CFTR.
• Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations.
• There are four CFTR modulators for people with certain CFTR mutations:
• ivacaftor (Kalydeco®)
• lumacaftor/ivacaftor (Orkambi®)
• tezacaftor/ivacaftor (Symdeko®)
• elexacaftor/tezacaftor/ivacaftor (TrikaftaTM)

Question 17

Discuss lung transplantation

Answer 17

• Lung transplantation is reserved for candidates who have exhausted all other alternative therapies.
• Universal criteria for lung transplantation in patients with CF are not available, but general considerations are: severely decreased lung function with the requirement for supplemental oxygen, and evidence of hypercarbia accompanied by progressive worsening of the disease.
• Absolute and relative contraindications to bilateral lung transplant are more defined.
• Absolute contraindications include sepsis, multiple organ dysfunction, documented history of non-adherence to treatment, patients colonised with Burkholderia cepacia class III obesity (body mass index [BMI] 40 or above), and refractory gastro-oesophageal reflux.
• Relative contraindications to transplant as it relates to CF patients are renal insufficiency (glomerular filtration rate <25 mL/minute and/or evidence of structural renal disease), exceedingly poor functional status with inability to consistently walk >600 feet on a standard 6-minute walk test, a history of pleurodesis, severe malnutrition with BMI <16, fungal infection, and poorly controlled diabetes mellitus.

Question 18

Discuss management of acute pulmonary exacerbation

Answer 18

• Antibiotic therapy is indicated in patients with pulmonary exacerbation; use is based on sputum culture results and sensitivities, along with clinical improvement with use of these medications.
• Medication choice is based on known or presumed bacterial colonisation.
• Antibiotics can be given orally, intravenously, inhaled, or in combination.
• Mild exacerbations generally respond to an oral antibiotic with or without inhaled tobramycin.
• Oral antibiotics include amoxicillin/clavulanic acid, amoxicillin, trimethoprim/sulfamethoxazole (co-trimoxazole), linezolid, and ciprofloxacin.
• The general duration of antibiotic therapy is 14 days.
• Moderate and severe exacerbations are treated with intravenous antibiotics. An aminoglycoside such as tobramycin is usually combined with one or two antibiotics with Staphylococcus or Pseudomonas coverage, depending on suspected or known colonisation and severity of the exacerbation.

Question 19

Discuss the treatment of pancreatic insufficiency

Answer 19

• Pancreatic enzyme replacement therapy and fat-soluble vitamin supplementation are indicated to support growth and nutrition. Enzyme replacements consist of lipase, protease, and amylase. Enzymes are given before snacks and meals with dose adjustments made based on food portions.
• Fat-soluble vitamins include vitamins A, D, E, and K. They are given on a regular basis with frequency based on CF nutritional recommendations.
• In general, serum blood levels are used to assess vitamin A, D, and E levels, while prothrombin time is used to assess vitamin K levels.
• H2 antagonists or proton-pump inhibitors are also used in these patients to provide a more alkaline environment for pancreatic enzyme supplemental therapy, thus improving enzyme function.

Question 20

Discuss liver disease in CF

Answer 20

• Approximately one third of patients may develop liver disease.
• In these patients, obstruction of biliary ducts leads to periportal inflammation and fibrosis.
• Eventually, this focal process may extend to become multilobular cirrhosis associated with portal hypertension.
• Advanced liver disease is the most common non-pulmonary cause of death in CF, accounting for approximately 2.5% of mortality.
• Therapy for hepatobiliary disease is limited to administration of oral bile acids (e.g., ursodeoxycholic acid).

Question 21

Discuss Intestinal disease in CF

Answer 21

• Abnormal salt and water balance in the intestine can lead to inspissations of stool and intestinal mucus resulting in intestinal obstruction, usually in the terminal ileum.
• Known as meconium ileus in the neonate and distal intestinal obstruction syndrome after the neonatal period, these obstructive episodes are usually partial obstructions and can be managed medically using water-soluble contrast enemas and oral administration of osmotic agents.
• Surgery is indicated in some situations, such as complete intestinal obstruction, signs of peritonitis, or failure of medical management.
• In addition to obstruction syndromes due to inspissations of stool, patients are at increased risk of intussusception.

Question 22

How does CF affect the reproductive systems

Answer 22

In men:
Sperm duct is blocked and prevents movement
Vans deferent can also just be absent

In women:
Levels of mucus vary in menstrual cycle
Women with CF have thick levels of mucus which can block cervix, preventing passage of sperm

Question 23

Discuss long term management of CF

Answer 23

• There is no cure, and therefore long-term care is a cornerstone of successful disease management.
• Patients should be seen by a CF care team at a CF centre at least
once every 3 months.
• At each visit, patients should have a history and physical examination performed by a specialised CF physician.
• They should also be evaluated by a nutritionist or registered dietician with speciality care in CF.
• If possible, patients should perform spirometry to monitor lung function.
• On a yearly basis and when clinical symptoms dictate, a chest x-ray, blood work (including full blood count, liver function tests, coagulation profile, vitamin A, D, and E levels), and full pulmonary function testing (including measurement of lung volumes and diffusing capacity) should be performed.
• Intravenous aminoglycosides are commonly used to treat lung infections.
• In CF patients, disease-specific changes can result in accelerated aminoglycoside
clearance.
• Therefore, higher doses are frequently needed to reach therapeutic drug levels.
• This,combinedwithrepeatedandoftenprolongedcoursesoftreatment,means that serum aminoglycoside levels must be carefully monitored.
• Hearing screens should be performed at least annually on all CF patients receiving aminoglycosides.
• Levels of nephrotoxic antibiotics should be monitored while the patient is on therapy.
• Serum creatinine levels should be checked weekly in these patients, and antibiotic doses should be adjusted accordingly.

Question 24

What is the prognosis for someone with CF

Answer 24

• This is a genetic disease for which there is no cure.
• However, the outlook for patients with this condition has greatly improved.
• In the past 50 years, the mean age of survival has risen from infancy/school age to almost 40 years old.
• This extraordinary improvement is due to the combined efforts of clinical carers, scientists, families, and foundations who together have established universal best practices for CF care.
• Many new, beneficial therapies have emerged over the past 5 decades.
• One factor that makes patients’ outlook so bright is the CF therapeutics pipeline established by the Cystic Fibrosis Foundation to bring novel therapies to the bedside in a scientifically rigorous and expedited fashion.
• The outlook for patients with CF has never been more optimistic, and there ought to be continued gains in the treatment of CF in the future.

Question 25

Summarise CF

Answer 25

• Genetic multisystem disease associated with abnormalities in salt and water transport across epithelial surfaces.
• Age of onset of symptoms is often in early infancy; however, in milder cases, symptoms may not develop until later childhood.
• Implementation of newborn screening in some countries allows for early detection and treatment.
• A sweat test is the most conclusive test for diagnosis and is performed in addition to genetic testing.
• Respiratory disease treatment includes mucus thinners, airway clearance, and antibiotics.
• Gastrointestinal disease is treated with supplemental pancreatic enzymes, calories, and fat-soluble vitamins to support growth and nutrition.
• Although severely life-shortening, in the past 50 years average survival has increased dramatically to almost 40 years of age.
• A range of new drugs are either in development or already approved for use by patients.
• This includes drugs that restore proper function of the defective protein that causes cystic fibrosis, and drugs that have a direct effect on mucociliary clearance.

Question 25

Summarise CF

Answer 25

• Genetic multisystem disease associated with abnormalities in salt and water transport across epithelial surfaces.
• Age of onset of symptoms is often in early infancy; however, in milder cases, symptoms may not develop until later childhood.
• Implementation of newborn screening in some countries allows for early detection and treatment.
• A sweat test is the most conclusive test for diagnosis and is performed in addition to genetic testing.
• Respiratory disease treatment includes mucus thinners, airway clearance, and antibiotics.
• Gastrointestinal disease is treated with supplemental pancreatic enzymes, calories, and fat-soluble vitamins to support growth and nutrition.
• Although severely life-shortening, in the past 50 years average survival has increased dramatically to almost 40 years of age.
• A range of new drugs are either in development or already approved for use by patients.
• This includes drugs that restore proper function of the defective protein that causes cystic fibrosis, and drugs that have a direct effect on mucociliary clearance.