Cystic Fibrosis

Definition, Etiology, PathogenesisTop

Cystic fibrosis (CF) is a genetic disorder causing abnormal secretion of the exocrine glands, mainly affecting the respiratory and gastrointestinal (GI) systems. It is an autosomal recessive condition caused by sequence variants of the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR; a cellular membrane protein that acts on chloride ion channels in epithelial cells). Synthesis of the defective protein affects the transmembrane transport of sodium and chloride, resulting in lumen dehydration and reduction in water content of exocrine secretions and mucus. High concentrations of sodium chloride inactivate the enzymes and proteins involved in local response to infection.

Abnormalities of the respiratory system include increased mucus secretion and retention with secondary chronic infections leading to mucus plugging, segmental atelectasis, bronchiectasis, and cysts (subpleural cysts may lead to pneumothoraxes).

Abnormalities of the GI system affect the pancreas and include retention of pancreatic secretions, activation of proteolytic enzymes, inflammation, and dilation of the pancreatic ducts with fibrosis, resulting in pancreatic exocrine insufficiency and CF-related diabetes mellitus. Areas of steatosis and biliary cirrhosis, which may progress to cirrhosis, are found in the liver. The presence of thick secretions in the intestines may cause any combination of abdominal pain, bowel obstruction, gastroenteritis, colitis, meconium ileus (in newborns), and distal intestinal obstruction syndrome (DIOS).

Effects on other organs include obliteration and hypoplasia of the vas deferens (resulting in male infertility). Impaired chloride reabsorption in the sweat glands leads to elevated sweat chloride levels and salty sweat. Chronic rhinosinusitis and nasal polyps are common. Reduced bone mineral density is also common, leading to increased rates of fractures and kyphoscoliosis.

Clinical Features and Natural HistoryTop

1. Symptoms:

1) Pulmonary symptoms: Chronic cough is usually the presenting pulmonary symptom. It is associated with the production of thick purulent sputum (frequently upon awakening). Other symptoms include dyspnea, wheeze, chest congestion, nasal congestion with chronic purulent secretions, epistaxis, and hemoptysis.

2) Extrapulmonary symptoms: Patients often experience some form of sinus disease, which can manifest as nasal congestion, headaches, cough (upper airway cough syndrome triggered by postnasal drip), or acute sinus infections. GI manifestations are also common and include passage of bulky and foul-smelling stools (indicative of pancreatic insufficiency), flatulence, abdominal pain, bloating, and constipation. Weight loss and failure to grow are common presenting features, especially in children. Lung disease may lead to pulmonary hypertension and its sequelae.

2. Physical findings: Rhonchi, rales, coarse breath sounds (upper lobe predominance), clubbing of digits, nasal polyps, and low body weight are common.

3. Natural history: The disease usually manifests in early childhood or infancy, uncommonly at a later age (in such cases it is associated with less severe and atypical symptoms). Typically the condition causes chronic destruction of the airways with subsequent involvement of the pulmonary parenchyma, ultimately leading to respiratory failure and death. The median age of survival (the age beyond which we expect 50% of babies with CF born today to live) in 2022 in Canada was 60 years.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to indirectness. Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2017 Annual Data Report. Accessed May 8, 2021. https://www.cysticfibrosis.ca/registry/2019AnnualDataReport.pdf

4. Pulmonary exacerbations: Deterioration of performance status, worsening cough, increased production of purulent sputum, chest congestion, fever, and increased dyspnea are usually accompanied by varying progression of the auscultatory, spirometric, and radiographic abnormalities and new or increased activity of pathogens appearing in the sputum. Sometimes a rapid decline in forced expiratory volume in 1 second (FEV1), even in the absence of symptoms, may be considered an exacerbation.

DiagnosisTop

Diagnosis is suggested by clinical symptoms or by the diagnosis of CF in siblings.

1. Diagnosis is confirmed when both of the following criteria are met:

1) Evidence of CFTR dysfunction, including ≥1 sweat chloride [Cl] concentration ≥60 mmol/L in 2 measurements carried out on different days, demonstration of pathologic sequence variants of both CFTR alleles (one from each parent), and/or abnormal nasal transepithelial electrical potential difference or transepithelial potential difference in rectal mucosa biopsy.

2) Other features of CF, including ≥1 positive newborn screen, features consistent with CF, or a positive family history.

2. Other diagnostic tests:

1) Chest radiographs and high-resolution computed tomography (HRCT) reveal pulmonary abnormalities (depending on the stage of the disease, the earliest and most severe findings are usually observed in the upper lobes), including various combinations of airway thickening, dilation of the bronchi (bronchiectasis), subpleural cysts or bullae, peripheral circular or linear opacifications, centrilobular nodularity with a “tree-in-bud” appearance, hilar lymphadenopathy, and pneumothorax. Computed tomography (CT) of the sinuses may be considered for assessment of sinus opacification to assist with diagnosis or to characterize the extent of sinus involvement.

2) Lung function tests can reveal obstructive respiratory flow pattern (low FEV1/forced vital capacity [FVC]) with significant hyperinflation (increased total lung capacity [TLC], functional residual capacity [FRC], residual volume [RV], and RV/TLC ratio). Repeat spirometry at every visit and full pulmonary function testing on a yearly basis are recommended.

3) Sputum microbiology (or less frequently bronchoalveolar lavage, throat swab): Bacterial infection is initially caused by Staphylococcus aureus or Haemophilus influenzae and later Pseudomonas aeruginosa (PsA). Less prevalent pathogens include Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Aspergillus species, and Burkholderia cepacia complex. Sputum is usually sent for culture every 3 to 6 months and during pulmonary exacerbations.

4) Laboratory tests:

a) Reduced fecal levels of elastase, with increased fecal excretion of fats (72-h fecal fat collection).

b) Increased serum liver enzyme levels (particularly alkaline phosphatase [ALP]).

c) Increased erythrocyte sedimentation rate, C-reactive protein (CRP), and white blood cell counts (during exacerbations).

d) Oral glucose tolerance test (OGTT) (repeat every year, as this allows for early diagnosis of CF-related diabetes); glycated hemoglobin (HbA1c) determination can be used for screening.

e) Pulse oximetry, arterial blood gases (when hypoxemic), or both. Routine blood testing including fat-soluble vitamin levels (A, D, E, K) should be performed yearly.

5) Ultrasonography to assess the liver if liver enzymes are abnormal. In children ultrasonography can be used for screening.

6) Bone densitometry (suggested every 1-5 years depending on T or Z scores).

TreatmentTop

Nonpharmacologic Management

1. Respiratory physiotherapy (active cycle of breathing techniques and use of simple support devices [eg, Flutter, Acapella]) repeated systematically several times, usually twice a day, is recommended. Earlier physiotherapy studies demonstrated variable improvement in pulmonary function, reduction of daily symptoms, increase in sputum expectorated, and decrease in the number of future pulmonary exacerbations. During exacerbations, physiotherapy should be intensified (3-4 times a day), particularly in patients with atelectasis or mucus plugging. A regular exercise program is indicated in all patients, especially those who have dyspnea or more severe disease.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness regarding long-term effects and variable results. Radtke T, Nolan SJ, Hebestreit H, Kriemler S. Physical exercise training for cystic fibrosis. Cochrane Database Syst Rev. 2015 Jun 28;6:CD002768. doi:10.1002/14651858.CD002768.pub3. PMID: 26116828. Psychologic assessment and counseling is important, as anxiety, depression, or both are prevalent, especially in those with moderate to severe disease.

2. Nutritional management: Suggest a high-protein, high-fat (35%-40% of calories from fat), and high-calorie (130%-150% of normal daily requirement) diet, targeting a body mass index (BMI) percentile >50%. Patients on CFTR modulators often experience weight gain, most with improvement into a normal BMI range; however, there are patients who have an elevated BMI. So far there has been no evidence-based nutritional guidance for those receiving modulators. In general, a more balanced diet should be recommended in patients with an elevated BMI.

3. Vaccination: All vaccines should be administered as in the general population, with particular emphasis on vaccination against pertussis and measles. Patients with liver disease should receive vaccination coverage against hepatitis A and B. All patients should be vaccinated against influenza and coronavirus disease 2019 (COVID-19) every year.

4. Oxygen therapy: Recommended for patients who are hypoxemic (PaO2 ≤55 mm Hg, SpO2 <88%); it may also improve exercise performance in those who demonstrate hypoxemia with physical activities.

Pharmacotherapy

1. Mucolytics (individual or combined): Inhaled dornase alpha 2.5 mg once daily (especially in patients with moderate to severe disease) has been shown to improve lung function and reduce the rate of exacerbations.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to the risk of bias. Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021 Mar 18;3(3):CD001127. doi: 10.1002/14651858.CD001127.pub5. PMID: 33735508; PMCID: PMC8094421. Inhaled hypertonic (3-5 mL of 3%-7%) saline has been shown to reduce pulmonary exacerbations and marginally improve lung function.Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2018 Sep 27;9(9):CD001506. doi: 10.1002/14651858.CD001506.pub4. PMID: 30260472; PMCID: PMC6513595. An inhaled beta2-agonist must be administered before inhalation of mucolytics. Patients who are on modulator therapy should continue routine airway clearance despite reduced sputum production. Some patients may choose to stop these therapies since they no longer produce any mucus while on modulator therapy.

2. Bronchodilators are commonly used before the administration of inhaled mucolytics, physiotherapy, inhaled saline solutions, or prior to exercising in patients who have shown postbronchodilator improvement of symptoms or spirometry results.

3. Inhaled glucocorticoids: Only in patients with coexistent asthma or allergic bronchopulmonary aspergillosis (ABPA).

4. Pancreatic enzymes (for patients with pancreatic insufficiency) should be administered with each meal at individually adjusted doses. In adults the starting dose is 500 IU of lipase/kg per meal and 250 IU/kg with snacks. If necessary, increase the dose by 150 to 250 IU/kg per meal to a maximum of 2500 IU/kg per meal (do not exceed 7000-12,000 IU/kg/d).

5. Fat-soluble vitamins A, D, E, and K are recommended daily. Their doses should be adjusted based on serum vitamin levels or evidence of end-organ damage (CF-related liver or bone disease). The vitamins should be taken together with pancreatic enzymes.

6. Long-term inhaled antimicrobial treatment: Inhaled tobramycin (300 mg nebulized bid for 1 month) is recommended in patients aged ≥6 years for the eradication of PsA after the first documented culture of sputum or throat swab. For patients with CF who are chronically infected with PsA, tobramycin (300 mg nebulized bid) administered in 1-month cycles (on alternating months) has been shown to be effective in maintaining or improving lung function, reducing respiratory symptoms, and reducing the risk for future pulmonary exacerbations. Tobramycin via a dry powder inhaler (4 capsules or 112 mg bid) has shown similar results in comparison with tobramycin inhaled solution (TIS). Inhaled aztreonam, colistin, and levofloxacin regimens via nebulizer systems have also been developed for chronic treatment of PsA infection in CF with similar results to those of TIS. For patients with CF who have more frequent pulmonary exacerbations or more severe pulmonary impairment, continuous inhaled antibiotics are often prescribed.Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of intervention). Quality of Evidence lowered due to the risk of bias. Smith S, Rowbotham NJ, Regan KH. Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2018 Mar 30;3(3):CD001021. doi: 10.1002/14651858.CD001021.pub3. PMID: 29607494; PMCID: PMC8407188. Long-term administration of oral antibiotics for the treatment of chronic Staphylococcus aureus infection is not recommended.

7. Long-term macrolide therapy: Azithromycin 250 daily or 500 mg thrice weekly is recommended in patients who are chronically infected with Pseudomonas spp.Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered because long-term effects are not clear. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012 Nov 14;11:CD002203. doi:10.1002/14651858.CD002203.pub4. Review. PMID: 23152214. This may be beneficial in the long term in patients with more advanced lung disease and in those who are prone to more frequent pulmonary exacerbations. Clinical effectiveness should be reevaluated every 6 to 12 months. Before the initiation of long-term treatment, sputum tests must be performed to exclude nontuberculous mycobacterial (NTM) infection. Repeat sputum testing for NTM should be performed every 6 months thereafter while receiving azithromycin.

8. CFTR modulators: CFTR modulators aim to improve CFTR function by targeting the underlying protein defect that causes CF. There are 2 classes of CFTR modulators: CFTR correctors and potentiators. Correctors are agents that increase the delivery and amount of functional CFTR protein to the cell surface, resulting in increased ion transport. Potentiators increase the ion channel activity of CFTR protein located at the cell surface, resulting in increased ion transport. CFTR modulators have led to significant improvements in lung function, rate and severity of pulmonary exacerbations, quality of life, weight gain, respiratory symptoms, and sweat chloride concentration. With the advent of novel combination treatments, ~90% of patients with CF are now eligible for CFTR modulator therapy. These new therapies have proven to be highly efficacious, although their cost remains high and likely prohibitive in many jurisdictions.

1) Elexacaftor/tezacaftor/ivacaftor (ETI) (trade name Trikafta) taken orally (2 tablets [elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg] in the morning and 1 tablet [ivacaftor 150 mg] in the evening, 12 h apart). The triple therapy combination regimen has been shown clinically effective in patients with CF aged ≥2 years who carry ≥1 copy of the delF508 variant.Evidence 7High Quality of Evidence (high confidence that we know true effects of the intervention).  Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819. doi: 10.1056/NEJMoa1908639. Epub 2019 Oct 31. PMID: 31697873; PMCID: PMC7282384. It is superior to the below listed combinations in terms of lung function improvement, symptom control, sweat chloride decrease, and reduction in pulmonary exacerbations. Of note, ETI needs to be taken with ≥8 g of fat and pancreatic enzymes to be properly absorbed.

2) Ivacaftor (trade name Kalydeco) is taken orally bid (150 mg for patients aged ≥6 years; 75 mg [weight >14 kg] or 50 mg [weight 7-14 kg] for those aged 12 months to 6 years). It is a CFTR potentiator that has been shown to be clinically effective in CF patients with ≥1 G55ID (class III) CFTR variant (5%-10% of patients with CF).Evidence 8High Quality of Evidence (high confidence that we know true effects of the intervention). Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185. PMID: 22047557; PMCID: PMC3230303. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825. PMID: 21083385; PMCID: PMC3148255.

3) Lumacaftor/ivacaftor (trade name Orkambi) is a first-generation combination CFTR corrector/potentiator that has been shown clinically effective in patients with CF who are homozygous for F508del (50%-60% of patients with CF; class II variant).Evidence 9High Quality of Evidence (high confidence that we know true effects of the intervention). Konstan MW, McKone EF, Moss RB, et at. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017 Feb;5(2):107-118. doi: 10.1016/S2213-2600(16)30427-1. Epub 2016 Dec 21. PMID: 28011037. Wainwright CE, Elborn JS, Ramsey BW, et al; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17. PMID: 25981758; PMCID: PMC4764353. This therapy is rarely used, as more effective modulator therapies are available.

4) Tezacaftor/ivacaftor (trade name Symdeko) taken orally (1 tablet [tezacaftor 100 mg/ivacaftor 150 mg] in the morning and 1 tablet [ivacaftor 150 mg] in the evening, 12 h apart). It is a second-generation combination CFTR corrector/potentiator that has been shown clinically effective in patients with CF aged ≥12 years who are either homozygous or heterozygous for the F508del variant.Evidence 10High Quality of Evidence (high confidence that we know true effects of the intervention). Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3. PMID: 29099344. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024-2035. doi: 10.1056/NEJMoa1709847. Epub 2017 Nov 3. PMID: 29099333; PMCID: PMC6472479.

The above pharmacotherapy may cause side effects and adverse reactions:

1) Liver enzymes/bilirubin elevation: Both elevated transaminases and an isolated rise in bilirubin have been seen with CFTR modulators. This can occur at any time during treatment. The degree of elevation helps determine if therapy needs to be held, reduced, or discontinued entirely. In patients with moderate to severe CF-related liver disease, empiric dose reduction is recommended, as outlined in the Cystic Fibrosis Canada guidelines.

2) Rash or hypersensitivity reactions: Rash is a fairly common adverse effect, while hypersensitivity reactions remain rare. Most rashes are mild and resolve without intervention. If the reaction is serious, treatment should be interrupted. Modulator therapy can be retried with close monitoring.

3) Drop in lung function and worsening respiratory symptoms: Symptoms including chest tightness, dyspnea, and reductions in FEV1 have been reported with lumacaftor/ivacaftor (Orkambi) but not with other modulators.

4) GI-related adverse effects: Abdominal pain, diarrhea, constipation, nausea, and vomiting have all been reported but rarely require therapy discontinuation.

5) Hypertension: Reported in trials for lumacaftor/ivacaftor (Orkambi) and ETI (Trikafta); 4% of patients on Trikafta had elevated systolic blood pressure (SBP) >140 mm Hg. There have also been reports of benign intracranial hypertension on modulator therapy, often in the setting of hypervitaminosis A. Some patients required discontinuation of ETI, while others improved with reduction of vitamin A.

6) Creatine kinase (CK) elevation: Reported in clinical trials for modulators. Typically CK levels fluctuate greatly with exercise; however, if the elevation is significant, it can warrant interruption of the therapy or its stopping.

7) Mental health concerns: There is a potential association of many mental health concerns with all available modulators, including mood changes, anxiety, sleep disturbances, brain fog, and suicidality. A recent study found no causal relationship between ETI (Trikafta) and depression-related events as well as suicidality. Mental health remains complex in patients on modulator therapy given the possible drastic changes to how their life may differ with improved clinical status. Yearly mental health screening is recommended using Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7).

8) Cataracts: CFTR modulators have been associated with cataracts in children. It is advised that infants born to mothers on modulator therapy are assessed by an ophthalmologist. This has not been shown in adults.

9) Drug–drug interactions: Ivacaftor, elexacaftor, and tezacaftor are all substrates of cytochrome P450 enzyme CYP3A. Recommendations are available as to how to adjust dosing if the drugs are given concurrently with CYP3A inducers or inhibitors. Consultation with a pharmacist is recommended.

10) Female fertility considerations: Modulators may increase fertility in women with CF (improvement in clinical status and changes to mucus in the cervix and uterus). It is important to counsel women regarding contraception.

Treatment of Pulmonary Exacerbations

1. Complete workup: Further investigations with radiography, sputum culture, nasal swab for viruses, complete blood count (CBC), CRP, and additional bloodwork as required depending on the severity of illness. If possible, it is very helpful to obtain spirometry and compare new results with the previous or baseline ones.

2. Intensification of physiotherapy, particularly in patients with atelectasis. This should be performed in combination with the use of nebulized mucolytic therapy.

3. Infection control: Patients with CF can have respiratory pathogens that are transmissible even if prior sputum cultures did not show this. For this reason it is recommended that health care providers in all settings should implement contact precautions (gloves and gown). This is to protect patients from getting hospital-acquired infections.

4. Pharmacotherapy:

1) Early treatment with an antibiotic (IV or oral, frequently plus inhaled, but not an inhaled antibiotic alone) for ≥10 days (14-21 days on average). While waiting for sputum culture results, use combined empiric treatment to cover H influenzae and S aureus as well as PsA. In patients with more severe exacerbations, administer IV beta-lactams (eg, ceftazidime, piperacillin) combined with an aminoglycoside. Alternatively, carbapenems (imipenem or meropenem) or aztreonam may be used. Clinical improvement is usually achieved no earlier than after 4 to 7 days of treatment. Of note, patients with CF usually require higher doses of antibiotics, as they tend to metabolize antibiotics quickly (follow the Cystic Fibrosis Canada dosing guideline).

2) Glucocorticoids are not recommended, unless patients have coexisting asthma or allergic bronchopulmonary aspergillosis (ABPA).

5. Mechanical ventilation (usually noninvasive) is indicated in acute respiratory failure due to a reversible cause or in patients with chronic respiratory failure awaiting lung transplant.

6. Follow-up: Patients with CF and pulmonary exacerbations should be regularly reevaluated with physical examination, spirometry, and bloodwork. If they are not improving as expected after 1 week, the plan should be reassessed and discussed with a CF specialist.

Surgical Treatment

1. Hemoptysis: In patients with severe life-threatening hemoptysis, radiology-guided embolization and, if not effective or not available, lobectomy may be indicated. In less severe cases use IV antibiotics, as most often hemoptysis is driven by infection. You can also use vitamin K and tranexamic acid, either oral or inhaled (see Hemoptysis).

2. Refractory bronchopleural fistulas unresponsive to chest tube drainage may require surgical pleurodesis or bullectomy (or both). Consult a transplant thoracic surgeon before doing this, as it may affect future transplant options. In chronic respiratory failure, early referral for lung transplant should be considered.

3. Lung transplant referral should be discussed with patients aged ≥18 years no later than when FEV1 is <50% predicted and rapidly declining (>20% relative decline over 12 months), or FEV1 is <40% with markers of shortened survival (eg, 6-minute walk tests <400 m, hypoxemia, hypercarbia, pulmonary hypertension, BMI <18 kg/m2, >2 exacerbations per year requiring IV antibiotics, massive hemoptysis, pneumothorax). Patients should also be referred when FEV1 is <30% predicted regardless of other markers. Common CF-related modifiable barriers to lung transplant should be considered (but should not preclude referral), including nutritional status, diabetic management, deconditioning, mental health issues, and adherence to therapies.

CF-Related Diabetes

CF-related diabetes is a unique form of diabetes that is different than type 1 and type 2 diabetes. It can be associated with both endocrine and exocrine pancreatic dysfunction. The main driver is typically insufficient insulin secretion; however, insulin resistance can also be present.

An annual screening with HbA1c measurement is recommended starting at the age of 10 years. If HbA1c is between 5.5% and 6.4%, the patient should undergo a 75-g OGTT. If HbA1c is >6.4%, it is recommended to confirm the diagnosis with a second HbA1c measurement or an OGTT.

Treatment involves encouraging a healthy diet and exercise, along with insulin as a first-line pharmacologic therapy. There is no clear evidence for noninsulin antihyperglycemic therapy in CF-related diabetes; however, it may be considered by experienced practitioners under close supervision (see Cystic Fibrosis Canada guideline on the treatment of CF-related diabetes).

Pregnancy Considerations and Newborn Screening

1. Pregnant women: CFTR modulators cross the placenta and can be detected in breast milk. Real-world experience is limited. It appears that modulators are tolerated well during pregnancy. Discontinuing modulator therapy during pregnancy has been associated with a significant decline of clinical status. Most clinicians remain comfortable to continue modulator therapy throughout pregnancy, with some holding in the second trimester.

2. Newborns: Screening in newborns of mothers on CFTR modulators is considered unreliable. To avoid a false-negative result, it is recommended to pursue CFTR analysis regardless of the screening outcome. In terms of monitoring it is recommended to check liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], bilirubin) in the infant at birth, 1 month, and 3 months if the mother chooses to breastfeed. As cases of noncongenital cataracts have been reported in pediatric patients, baseline and follow-up ophthalmologic examinations are recommended (see Cystic Fibrosis Canada recommendations for mothers on CFTR modulators).

Follow-UpTop

Every 3 months assess nutritional status, perform spirometry, SpO2 measurement, and sputum microbiology. If the patient receives modulator therapy, assess CBC, ALT, AST, ALP, GGT, bilirubin, CK, sputum microbiology, and spirometry at baseline, 1 month, 3 months, and then every 3 months in the first year of therapy.

Every year blood testing should be performed with particular attention to assessing liver disease (ALT, AST, GGT), CF-related diabetes (HbA1c), fat-soluble vitamins, and nutritional status.

Every 5 years, starting at the age of 40 years, colonoscopy should be performed, as patients with CF are at greater risk of colon cancer.

In Canada, patients with CF should be regularly followed up in a specialized CF clinic. Visits usually occur every 3 months or more often in certain situations. Follow-up chest radiography should be performed in the case of severe exacerbations, suspected complications, or rapid decline in pulmonary function. Bone densitometry can be considered every 1 to 5 years depending on previous T/Z scores.

ComplicationsTop

Respiratory complications: Atelectasis, pneumothorax, hemoptysis, obstructive sleep apnea, allergic bronchopulmonary aspergillosis, pulmonary hypertension.

Extrapulmonary complications: Cor pulmonale, diabetes mellitus, cholelithiasis or cholangitis, fatty liver disease, cirrhosis, acute pancreatitis, DIOS, gastroesophageal reflux disease, hypertrophic osteoarthropathy, osteopenia or osteoporosis, infertility.