Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene on chromosome 7, which encodes the cystic fibrosis transmembrane conductance regulator — a chloride and bicarbonate channel expressed on the surface of epithelial cells throughout the body. A dysfunctional or absent CFTR channel disrupts normal salt and water transport across these epithelia, producing abnormally thick, dehydrated secretions wherever CFTR is expressed: the airways, the pancreatic ducts, the intestine, the bile ducts, the sweat glands, and the vas deferens.^[1] This single molecular defect is why CF is a genuinely multisystem disease rather than a lung disease with incidental complications elsewhere.

Normal versus defective CFTR channel function — a working channel lets chloride and water move freely across the epithelial surface; a defective channel blocks that flow, dehydrating the surface secretion into the thick mucus that drives CF lung, pancreatic, and GI disease. (Lbudd14, CC BY-SA 3.0, Wikimedia Commons)

CF is inherited in an autosomal recessive pattern — a child needs two CFTR mutant alleles, one from each parent, to be affected; a person with only one mutant allele is an unaffected carrier. F508del (also written ΔF508 or p.Phe508del) is by far the most common CFTR mutation worldwide, present on roughly two-thirds of CF alleles in populations of European descent, and found on at least one allele in around 90% of people with CF — a fact that matters directly for CFTR modulator eligibility (see Choose Initial Treatment).^[1] More than 2,000 CFTR variants have been catalogued, though a much smaller number are common enough to be clinically well-characterized.

Epidemiology and the modern outlook

Approximately 4,500 Canadians are living with CF today, with roughly 75 new diagnoses added in 2023 alone — more than half identified through newborn screening before symptoms ever appeared.^[2] As of 2023, every Canadian province and territory screens for CF as part of routine newborn screening — Alberta was first, in 2007, and Quebec was the last jurisdiction to join, in 2018 — meaning most Canadian children with CF are now identified in the first weeks of life rather than after a diagnostic delay driven by symptoms.^[2] The disease's trajectory has changed dramatically with the arrival of CFTR modulator therapy: a child born with CF in Canada in 2023 has a predicted median survival of 62.3 years, an improvement of nearly two and a half years over 2022 alone — among the fastest-improving prognoses of any genetic disease being actively tracked.^[2]

Why every organ system is on the table

Because CFTR is expressed so broadly, a single diagnosis carries disease across several organ systems, each covered in more depth in Recognize the Condition: pancreatic exocrine insufficiency affects 85-90% of people with CF and drives fat malabsorption and malnutrition unless corrected with enzyme replacement; meconium ileus is the presenting sign in roughly 10-20% of newborns with CF; CF-related diabetes (CFRD) — a distinct entity from type 1 or type 2 diabetes — develops in about 20% of adolescents and 40-50% of adults with CF; and male infertility from congenital bilateral absence of the vas deferens (CBAVD) affects the large majority of men with CF, even those with otherwise mild disease.^[3]

Atypical and CFTR-related disease

Not every CFTR mutation produces classic multisystem CF — some genotype combinations produce a milder, single-organ "CFTR-related disorder," such as isolated CBAVD, or recurrent idiopathic pancreatitis, with a normal or only mildly elevated sweat chloride. These patients need individualized specialist assessment rather than being forced into either a full CF or a no-CF label (see Assessment & Diagnosis).

• Two CFTR mutant alleles, one inherited from each parent — autosomal recessive inheritance means both parents of an affected child are obligate carriers, typically without any CF symptoms themselves.
• A sibling or other close relative with confirmed CF, or a family history of an unexplained CF-spectrum presentation (recurrent pancreatitis, unexplained bronchiectasis, male infertility from CBAVD) that was never formally worked up.
• Northern European ancestry carries the highest population carrier frequency, but CF occurs across every ethnic background — a lower prior probability is not the same as zero probability, and should not by itself delay testing in a patient with a compatible presentation.^[1]
• Consanguinity modestly increases the chance that both parents carry the same rare recessive allele.
• A positive newborn screen (elevated immunoreactive trypsinogen, with or without an identified CFTR mutation) — see Assessment & Diagnosis for the full screening-to-diagnosis pathway.

Why genotype, not just diagnosis, matters clinically

CFTR mutations are grouped into functional classes based on the specific defect they cause in the CFTR protein's production, folding, gating, or conductance — and this classification is not just an academic exercise, since it is what determines whether, and which, CFTR modulator a specific patient is eligible for (see Choose Initial Treatment).

In practice, F508del's own defect spans Class II, III, and VI mechanisms simultaneously, which is exactly why the most effective modulator regimens for F508del combine a corrector with a potentiator rather than using either alone.^[1]

Newborn screening — the entry point for most Canadian diagnoses

Every Canadian province and territory now screens newborns for CF, typically using a dried blood spot immunoreactive trypsinogen (IRT) level, followed by either a repeat IRT or a CFTR mutation panel on the same specimen if the first IRT is elevated. A positive screen is not a diagnosis — it triggers referral for a confirmatory sweat chloride test, ideally within the first weeks of life.^[2][5]

Sweat chloride testing — the diagnostic gold standard

Quantitative pilocarpine iontophoresis sweat chloride testing remains the reference standard for confirming or excluding CF, whether prompted by a positive newborn screen, a suggestive clinical presentation, or a family history.^[5]

^[5]

Genetic (CFTR mutation) testing

CFTR mutation analysis complements the sweat test — it confirms the genotype, informs CFTR modulator eligibility (see Choose Initial Treatment and the mutation-class table in Risk Factors), and supports genetic counseling and carrier testing for family members. Testing typically starts with a targeted panel covering the most common mutations and escalates to full gene sequencing if clinical suspicion remains high despite a negative or incomplete panel result.

Atypical presentations and CFTR-related disorders

A patient with a compatible single-organ presentation (isolated CBAVD, recurrent idiopathic pancreatitis, unexplained bronchiectasis) but a normal or intermediate sweat chloride may have a CFTR-related disorder rather than classic CF — refer to a CF centre for individualized genotype and phenotype assessment rather than forcing a binary diagnosis.

Differential diagnosis

Consider non-CF bronchiectasis, primary ciliary dyskinesia (especially with situs abnormalities or chronic otitis media), asthma, and, for a GI-predominant presentation, celiac disease or another cause of chronic pancreatitis — a compatible presentation without confirmatory sweat chloride and genetic testing should not be labelled CF.

Modern CF care is genuinely two-pronged, and both prongs are permanent — starting a CFTR modulator does not retire the second prong.

• Disease-modifying: correct the underlying CFTR protein defect with genotype-directed modulator therapy wherever the patient's genotype and age make them eligible, to slow or halt progressive organ damage rather than only treating its downstream consequences.
• Symptomatic/organ-specific, for every patient regardless of modulator eligibility: maintain lung function and prevent/treat pulmonary exacerbations; correct pancreatic exocrine insufficiency and fat-soluble vitamin deficiency; achieve and maintain normal growth and nutritional status; screen for and manage CF-related diabetes; monitor for and manage CF-associated liver disease; support fertility and family-planning decisions; and protect quality of life and mental health through a genuinely lifelong, high-burden treatment regimen.
• Prevent respiratory cross-infection between people with CF through infection-control practices specific to this population (see Non-Pharmacologic Treatment).
• Provide genetic counseling to patients and offer carrier testing to their family members.

Airway clearance

Daily airway clearance is core therapy, not an adjunct — chest physiotherapy, positive expiratory pressure (PEP) devices, oscillating PEP devices (e.g., Acapella, Flutter), high-frequency chest wall oscillation vests, and the active cycle of breathing technique are all reasonable options; the specific technique matters less than consistent daily adherence, and technique should be selected and taught by a CF-experienced respiratory therapist and reassessed at follow-up. Regular aerobic exercise adds airway-clearance benefit on top of a dedicated technique, not as a substitute for one.

Nutrition

Caloric requirements are substantially higher than average due to increased resting energy expenditure and ongoing malabsorption even with optimized PERT — many patients need well above 100% of the general-population recommended caloric intake, with a genuinely high-fat diet rather than the fat restriction typically counselled for the general population. Salt supplementation, especially for infants and during hot weather or heavy exertion, reduces the risk of salt-depletion dehydration from abnormally salty sweat losses. Track growth (children) and BMI/weight trend (all ages) at every visit — nutritional status is itself a strong predictor of long-term pulmonary outcomes.

Infection control — genuinely specific to CF care

People with CF are cohorted and separated from one another in clinical settings specifically to prevent person-to-person transmission of CF-relevant pathogens — Pseudomonas aeruginosa, Burkholderia cepacia complex, and MRSA among them — through individual exam rooms rather than shared waiting areas, minimum spacing between CF patients when a shared space cannot be avoided, no sharing of nebulizers or airway-clearance equipment between patients, and strict hand hygiene. This is not a generic infection-control reminder — it is a CF-specific practice built around documented person-to-person spread of these organisms within CF populations, and lapses have real long-term consequences for a newly-colonized patient.

Vaccination

Keep routine immunization current, and add annual influenza vaccination and age-appropriate pneumococcal vaccination given the added risk a respiratory infection poses in CF lung disease.

Genetic counseling and family planning

Offer carrier testing to siblings and other close relatives of a newly diagnosed patient, and provide reproductive counseling for patients themselves — including the CBAVD-driven male infertility discussed in Recognize the Condition, and preconception counseling for a patient or partner who may be a carrier.

Psychosocial support and treatment burden

The daily regimen in this chapter is genuinely demanding — multiple inhaled therapies, enzymes with every meal, daily airway clearance, and frequent clinic visits. Screen for anxiety and depression, which are more common in CF than in the general population, and involve CF-specific social work and psychology support proactively rather than only after adherence visibly breaks down.

Smoking, vaping, and secondhand smoke

Counsel against smoking and vaping, and counsel caregivers of children with CF specifically against secondhand smoke exposure in the home, given the added respiratory burden on already-vulnerable airways.

Pregnancy

Pregnancy is increasingly common in CF as overall health outcomes have improved. Current practice generally continues CFTR modulator therapy through pregnancy where the patient was already stable on it, since undertreated maternal lung disease and hypoxemia pose a real risk to the pregnancy, and accumulating observational data have not raised a clear signal of fetal harm — this remains an individualized, specialist-directed decision rather than a blanket rule. Continue PERT and fat-soluble vitamin supplementation unchanged. For an acute pulmonary exacerbation in pregnancy, select antibiotics with the same general pregnancy-safety principles used elsewhere in the platform (prefer beta-lactams; use a fluoroquinolone only when no suitable alternative exists and the infection risk clearly outweighs the theoretical risk, given how limited alternative antipseudomonal options are in CF).

Breastfeeding

Data on CFTR modulators in breastfeeding are limited; continuation is an individualized decision weighing the mother's own clinical need against the amount of available infant-exposure data for her specific regimen — involve the CF care team directly rather than defaulting to either continuing or stopping.

Pediatrics and infants

Most Canadian children are now diagnosed through newborn screening before symptoms appear (see Assessment & Diagnosis). Start CFTR modulator therapy at the youngest eligible age for the patient's genotype — the rationale is preventing damage before it starts, not simply treating it once present. Infants need PERT with every feed (formula or breastfeeding) from the point pancreatic insufficiency is confirmed, dosed per weight and adjusted to growth and stool pattern.

CF-related diabetes (CFRD) — a genuinely distinct entity, with its own new Canadian guideline

CFRD is not type 1 or type 2 diabetes wearing a CF label — its dominant mechanism is progressive pancreatic fibrosis and islet destruction rather than autoimmune beta-cell loss or primary insulin resistance, though insulin resistance can add to the picture during illness or corticosteroid exposure.^[3]

Canadian approach (2025) a 2-step screening algorithm starting at age 10: annual A1C as the first step, with an oral glucose tolerance test (OGTT) reserved for the subset with an indeterminate A1C in the 5.5-6.4% range — this differs meaningfully from the older American approach below, and reflects a genuinely Canadian clinical practice guideline rather than an adaptation of American recommendations.^[11]

Original American approach (2010, still widely referenced) annual OGTT as the primary screening test from age 10, given poor sensitivity of A1C alone for detecting CFRD in this population — also screen with 48 hours of fasting/2-hour postprandial glucose monitoring during any pulmonary exacerbation requiring IV antibiotics or systemic corticosteroids, since CFRD can first declare itself during acute illness.^[3]

Treatment insulin is first-line and standard of care once CFRD is diagnosed — oral hypoglycemic agents are not as effective for CFRD's nutritional and metabolic goals and are not recommended outside a research setting.^[3] Unlike standard diabetes counselling, do not restrict dietary fat or calories to manage CFRD — the high-calorie, high-fat nutritional targets in Non-Pharmacologic Treatment still apply, and insulin dosing is built around supporting that intake, not limiting it.

Lung transplant referral

Discuss lung transplantation as an option with every patient once FEV1 falls under 50% predicted, well before referral itself becomes urgent, and always after a trial of CFTR modulator therapy if the patient's genotype makes them eligible and this has not already been tried.

Base the decision on overall clinical trajectory rather than a single FEV1 value in isolation, and refer early for a second opinion if a patient has been declined elsewhere but a potentially reversible barrier to transplant exists.

Older adults

A genuinely new and growing population as modulator therapy extends survival — CF care teams are now managing complications of aging (malignancy risk, osteoporosis, cardiovascular disease) that were rarely seen in a CF population historically, and screening/prevention should not be deferred solely because the primary diagnosis is CF.

Hepatic impairment

Dose-reduce ivacaftor-containing modulator regimens in moderate hepatic impairment, and avoid or use with extreme caution in severe hepatic impairment, per the product monograph — this is a genuinely important adjustment distinct from the routine LFT-monitoring schedule that applies to every patient starting one of these regimens (see Choose Initial Treatment).

• Comprehensive CF clinic visit approximately every 3 months: spirometry, sputum/throat culture for surveillance (not only during an exacerbation), weight/BMI and growth parameters, and a review of adherence and technique for every component of the regimen.
• Liver function tests on the specific schedule in Choose Initial Treatment for any patient on an elexacaftor- or vanzacaftor-containing modulator regimen — baseline, monthly for 6 months, then quarterly for 12 months, then at least annually.
• Annual bloodwork: CBC, comprehensive metabolic panel, fat-soluble vitamin levels (A, 25-hydroxyvitamin D, E), and coagulation status if vitamin K status or liver disease is a concern.
• CFRD screening starting at age 10 per the algorithm in Special Populations, plus glucose monitoring during any pulmonary exacerbation requiring IV antibiotics or systemic corticosteroids.
• Annual chest imaging and pulmonary function trend review, with more frequent spirometry around any exacerbation or therapy change.
• Bone density (DEXA) screening starting in adolescence/early adulthood, given cumulative risk factors for reduced bone density (malabsorption, chronic inflammation, reduced activity in more advanced disease, corticosteroid exposure).
• Confirm annual influenza vaccination and age-appropriate pneumococcal vaccination status at a routine visit.
• For a patient managed non-operatively for DIOS, or with recurrent DIOS, confirm a daily bowel regimen is actually in place at follow-up rather than only discussed once (see Treatment Failure/Next Step).

1. Pulmonary exacerbation not improving on outpatient oral therapy: escalate to IV antibiotics rather than switching to a second oral agent empirically; confirm a culture was actually obtained before the first antibiotic was started, and adjust to susceptibilities once results return.
2. Recurrent exacerbations despite optimized modulator therapy and chronic maintenance regimen: reassess adherence and inhaled-therapy technique first — both are common, correctable causes of apparent treatment failure — then evaluate for a new or resistant pathogen (including nontuberculous mycobacteria), allergic bronchopulmonary aspergillosis, and declining pulmonary function trend that may warrant a lung transplant referral discussion (see Special Populations) rather than simply intensifying the same antibiotics again.
3. CFTR modulator with an inadequate clinical response or a tolerability problem: confirm adherence and confirm the genotype was actually eligible for the specific agent prescribed before assuming drug failure; check LFTs if hepatotoxicity is suspected and interrupt therapy per Choose Initial Treatment if significant elevation is found; do not stop the symptomatic regimen (PERT, airway clearance, chronic inhaled therapy) while troubleshooting the modulator.
4. Persistent steatorrhea or poor growth despite PERT: confirm dosing is actually being taken with every fat-containing meal and snack, not only "main meals," before increasing the dose toward (and never casually past) the fibrosing-colonopathy-associated upper limits in Choose Initial Treatment; consider concurrent acid suppression, since an overly acidic duodenal environment can inactivate enzyme preparations, and consider supplemental enteral nutrition (nasogastric or gastrostomy feeding) for persistent malnutrition despite these steps.
5. DIOS not resolving with oral polyethylene glycol or a Gastrografin-based enema: escalate to surgical consultation — medical management resolves the substantial majority of episodes, but a genuinely obstructed patient needs surgical evaluation rather than repeated conservative attempts.^[4]
6. New-onset hyperglycemia during a pulmonary exacerbation: treat with insulin for the duration of the acute illness even if it resolves afterward, and formally reassess for CFRD once the patient is clinically stable rather than assuming it was a one-time stress response.

• Stopping or reducing airway clearance, PERT, or chronic inhaled therapy once a patient starts a CFTR modulator — modulators are additive to, not a replacement for, the symptomatic regimen.
• Escalating PERT dose past the fibrosing-colonopathy-associated thresholds by default, rather than first reassessing timing, adherence, and acid suppression.
• Giving pancreatic enzymes on a fixed clock schedule rather than with the first bite of every fat-containing meal or snack.
• Starting chronic azithromycin without first screening sputum for nontuberculous mycobacteria.
• Prescribing oral hypoglycemic agents for CF-related diabetes instead of insulin.
• Applying a standard diabetes low-fat, calorie-restricted diet to a patient with CFRD, rather than maintaining the high-calorie, high-fat CF nutritional targets alongside insulin therapy.
• Missing the required liver-function monitoring schedule for a patient starting an elexacaftor- or vanzacaftor-containing modulator regimen.
• Starting empiric antibiotics for a suspected pulmonary exacerbation without first obtaining a sputum or throat culture.
• Treating right lower quadrant pain in a CF patient as routine constipation without considering DIOS, or conversely assuming DIOS without considering appendicitis or another true surgical abdomen.
• Lapses in CF-specific infection-control practice (shared clinic spaces, shared equipment) that create a real risk of new cross-infection with Pseudomonas aeruginosa or Burkholderia cepacia complex.
• Deferring genetic counseling and family carrier-testing discussion at diagnosis, or raising it once and never following up on whether it was completed.
• Assuming a patient with mild disease, or one on a modern modulator regimen, no longer needs routine CFRD, liver, and bone-density surveillance.

CFTR Modulators

Genotype-directed — confirm the patient's specific CFTR mutation(s) against the eligible-genotype list before prescribing. All ivacaftor-containing regimens require dosing with fat-containing food. See Choose Initial Treatment for the required liver-monitoring schedule.

Pancreatic Enzyme Replacement and Fat-Soluble Vitamins

For every patient with confirmed pancreatic exocrine insufficiency (85-90% of people with CF). Dose PERT with the first bite of every fat-containing meal or snack, not on a fixed clock.

Chronic Airway Clearance, Mucolytic, and Anti-Inflammatory Therapy

Give in the standard order — bronchodilator, then hypertonic saline, then dornase alfa, then airway clearance technique, then any inhaled antibiotic.

Chronic Suppressive (Maintenance) Antipseudomonal Inhaled Antibiotics

For chronic Pseudomonas aeruginosa airway colonization — typically alternating 28 days on/28 days off.

Acute Pulmonary Exacerbation — IV Antibiotic Therapy

Obtain a sputum or throat culture before starting. 10 days is not inferior to 14 for an early symptomatic/spirometric responder — do not extend by default. No routine adjunctive systemic corticosteroids.

CF-Related Diabetes and CF-Associated Liver Disease

Insulin is first-line for CFRD — oral hypoglycemic agents are not recommended outside a research setting. Do not restrict dietary fat/calories to manage CFRD.