Pulmonology

Cystic fibrosis: diagnosis, management, and complications

Clinical Overview and When to Suspect Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene (chromosome 7) → defective chloride/bicarbonate channel → thick, dehydrated secretions in lungs, pancreas, GI tract, liver, and reproductive organs.

Incidence ~1 in 3,000–4,000 live births in Caucasians; carrier frequency ~1 in 25

Most children now diagnosed via newborn screening (NBS) before symptoms develop

Board pearl: Suspect CF in any infant with meconium ileus — ~15–20% of CF patients present this way, and >90% of infants with meconium ileus have CF

Classic triad that should trigger evaluation: recurrent/chronic sinopulmonary disease + failure to thrive + steatorrhea (pancreatic insufficiency)

Other red flags: salty-tasting skin (parents report), rectal prolapse in a toddler, nasal polyps in a child <12 years, Pseudomonas aeruginosa in sputum of a young child, hyponatremic/hypochloremic metabolic alkalosis in an infant (pseudo-Bartter syndrome)

Airway pathology: defective Cl⁻ secretion + excessive Na⁺/H₂O reabsorption → dehydrated airway surface liquid → impaired mucociliary clearance → chronic infection and neutrophilic inflammation → bronchiectasis

History — Presentation Patterns by Age

The clinical history varies dramatically by age at presentation.

Newborn: meconium ileus (bilious vomiting, abdominal distension, failure to pass meconium in first 24–48 hours), prolonged neonatal jaundice

Infant: failure to thrive despite adequate caloric intake, steatorrhea (bulky, greasy, foul-smelling stools), recurrent respiratory infections, edema/hypoproteinemia (especially in breastfed infants — breast milk fat requires lipase for absorption)

Toddler/Preschool: rectal prolapse, chronic productive cough, recurrent pneumonia, nasal polyps, hepatomegaly

School-age/Adolescent: progressive bronchiectasis, digital clubbing, chronic sinusitis, DIOS (distal intestinal obstruction syndrome), CF-related diabetes (CFRD), delayed puberty

Clinical tip: Ask about stool pattern — parents often normalize chronic diarrhea; ask specifically about greasiness, floating stools, and frequency

Family history: consanguinity, sibling death in infancy, known CF carriers

Board pearl: Male infertility (obstructive azoospermia from congenital bilateral absence of vas deferens — CBAVD) affects >95% of CF males and can be the presenting feature in mild/atypical genotypes

Physical Exam — What to Look For at Every Visit

The physical exam in CF is a longitudinal tool — subtle changes indicate disease progression.

Growth: weight, length/height, and head circumference plotted serially; weight-for-length (infants) or BMI (≥2 years) — goal BMI ≥50th percentile

Respiratory: barrel chest (hyperinflation), retractions, crackles, wheeze; digital clubbing develops with chronic hypoxia/inflammation

ENT: nasal polyps (uncommon in healthy children — their presence <12 years is highly suspicious for CF), chronic rhinosinusitis with purulent drainage

Abdomen: hepatomegaly (focal biliary cirrhosis), palpable stool in RLQ (DIOS), rectal prolapse on straining

Skin: salty taste on kiss (↑ sweat Cl⁻), eczematous dermatitis from essential fatty acid deficiency

Board pearl: In an infant with edema + anemia + hypoalbuminemia → think CF with pancreatic insufficiency causing protein-calorie malnutrition — may mimic kwashiorkor

Musculoskeletal: hypertrophic osteoarthropathy in adolescents with advanced disease

Diagnostic Workup — Newborn Screening and Sweat Test

Diagnosis follows a stepwise approach: NBS → sweat chloride testing → CFTR genetic analysis.

→ Most states use IRT/IRT (two elevated IRT samples) or IRT/DNA (elevated IRT followed by CFTR mutation panel)

→ Positive NBS is NOT diagnostic — it is a screen; sweat test must follow

→ Normal: <30 mmol/L

→ Intermediate: 30–59 mmol/L → repeat + expanded genetic testing

→ Diagnostic of CF: ≥60 mmol/L on two separate occasions

Newborn screening: measures immunoreactive trypsinogen (IRT) from heel-stick blood; ↑ IRT reflects pancreatic injury in utero

Sweat chloride test (pilocarpine iontophoresis) — gold standard:

Board pearl: Sweat test should be performed at a CF Foundation–accredited center; minimum sweat volume required for valid result is 75 mg (or 15 μL); test is reliable after 2 weeks of age in a term infant ≥2 kg

False negatives: edema, insufficient sweat collection

False positives for ↑ sweat Cl⁻: adrenal insufficiency, hypothyroidism, ectodermal dysplasia, malnutrition, nephrogenic DI

Diagnostic Workup — Genetic Testing and Ancillary Studies

Genetic confirmation and baseline studies complete the diagnostic workup.

→ Standard panels test 23–40 common mutations; expanded sequencing if initial panel non-diagnostic

→ Two disease-causing CFTR mutations + clinical features or ↑ sweat Cl⁻ = confirmed CF

→ Fecal elastase-1: <200 μg/g = pancreatic insufficiency (present in ~85% of CF patients)

→ Fat-soluble vitamins: A, D, E, K levels — commonly deficient

→ Liver function tests, CBC

→ Oropharyngeal/sputum culture for respiratory pathogens (Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae)

→ Chest radiograph baseline

CFTR mutation analysis: >2,000 variants identified; F508del is the most common (~70% of alleles in Caucasians)

CFTR-related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID): intermediate sweat Cl⁻ + 0 or 1 CFTR mutation → requires longitudinal follow-up

Ancillary baseline studies at diagnosis:

Board pearl: Spirometry (FEV₁) is the primary measure of lung function but is generally reliable only in children ≥6 years; perform at every quarterly visit once feasible

Pulmonary Management — Airway Clearance and Mucolytics

The cornerstone of CF lung therapy is clearing thick secretions and breaking the infection-inflammation cycle.

→ Infants: chest physiotherapy (CPT) with percussion and postural drainage

→ Older children/adolescents: oscillatory positive expiratory pressure devices (e.g., flutter valve), high-frequency chest wall oscillation (vest therapy), active cycle of breathing

→ Dornase alfa (recombinant DNase): inhaled daily — cleaves extracellular DNA from neutrophils → ↓ sputum viscosity → shown to improve FEV₁; recommended for all CF patients ≥6 years

→ Hypertonic saline (7%): inhaled BID — osmotically draws water into airway → improves mucociliary clearance; can be used in infants

Airway clearance therapy (ACT): recommended at least twice daily, even when asymptomatic

Mucolytics:

Board pearl: Dornase alfa is CF-specific — do NOT use in non-CF bronchiectasis (no benefit). Hypertonic saline should be preceded by bronchodilator to prevent bronchospasm

Order of inhaled therapies: bronchodilator → hypertonic saline → dornase alfa → airway clearance → inhaled antibiotic

Pulmonary Management — Chronic Infection and Anti-inflammatory Therapy

Chronic airway infection drives progressive lung destruction; treatment targets key CF pathogens.

→ Anti-staphylococcal antibiotics for positive cultures; prophylactic anti-staph therapy is NOT universally recommended (varies by center)

→ Chronic Pseudomonas: inhaled tobramycin or aztreonam lysine on alternating months

→ Azithromycin (3 days/week): immunomodulatory — ↓ exacerbations, modest ↑ FEV₁; recommended for chronic Pseudomonas and considered in others ≥6 years

→ Ibuprofen (high-dose): slows FEV₁ decline in 6–17 year olds but requires pharmacokinetic monitoring → limited use

Early childhood: Staphylococcus aureus is the most common initial pathogen; Haemophilus influenzae also common

Pseudomonas aeruginosa: acquisition is a critical milestone → early eradication with inhaled tobramycin (28 days on/28 days off) is standard

MRSA: associated with worse pulmonary outcomes; treatment varies but may include TMP-SMX, linezolid, or vancomycin for exacerbations

Anti-inflammatory:

Board pearl: Burkholderia cepacia complex — associated with rapid pulmonary decline and is a relative contraindication to lung transplantation; strict infection control to prevent patient-to-patient transmission

CFTR Modulator Therapy — Transforming CF Care

CFTR modulators target the underlying protein defect and have dramatically improved outcomes.

→ Class I–III: minimal or no functional CFTR at cell surface (includes F508del, G551D)

→ Class IV–VI: some residual CFTR function

→ Potentiators (e.g., ivacaftor): ↑ channel open probability of CFTR at cell surface — effective for gating mutations (G551D)

→ Correctors (e.g., lumacaftor, tezacaftor, elexacaftor): help misfolded CFTR protein reach cell surface — most effective combined with potentiator

→ ↑ FEV₁ by ~10–14%, ↓ sweat Cl⁻ by ~40 mmol/L, ↓ pulmonary exacerbations by ~60%, improved BMI and quality of life

Classes of CFTR mutations (simplified):

Modulator types:

Elexacaftor/tezacaftor/ivacaftor (ETI, "Trikafta"): triple combination; approved for ≥2 years with at least one F508del allele (~90% of CF population eligible)

Board pearl: CFTR modulators do NOT cure CF — patients still require airway clearance, monitoring, and pancreatic enzyme replacement; however, ETI has changed the disease trajectory profoundly

Side effects: hepatotoxicity (monitor LFTs), cataracts in children (ophthalmologic screening), rash; drug interactions via CYP3A

Age-Specific Considerations — Neonates and Infants

Early diagnosis through NBS allows proactive management before irreversible lung damage.

→ Meconium ileus: diagnosed by contrast enema (microcolon + meconium pellets); uncomplicated cases may resolve with hyperosmolar enema (Gastrografin); complicated (perforation, volvulus, atresia) requires surgical intervention

→ Sweat test valid at ≥2 weeks of age and ≥2 kg body weight; earlier testing → higher false-negative rate

→ Start pancreatic enzyme replacement therapy (PERT) immediately if fecal elastase <200 μg/g

→ Nutritional management is paramount — breast milk or standard formula + PERT; high-calorie formula if needed

→ Fat-soluble vitamin supplementation (A, D, E, K) from diagnosis

→ Airway clearance: CPT with percussion/postural drainage; hypertonic saline nebulization can be used

→ Respiratory cultures via oropharyngeal swab (cannot expectorate) at every visit

Neonates:

Infants:

Board pearl: CF infants can develop severe hyponatremic, hypochloremic metabolic alkalosis from excessive sweat salt losses — especially in hot weather or with gastroenteritis → replace NaCl (1–2 mEq/kg/day supplementation typical)

Age-Specific Considerations — Children and Adolescents

As children grow, the focus shifts to lung function preservation, nutritional optimization, and psychosocial support.

→ Spirometry every 3 months — FEV₁ is the primary outcome measure; percent predicted FEV₁ ≥80% is the goal

→ Transition from CPT to independent airway clearance techniques (vest, PEP device)

→ Screen for CF-related liver disease (hepatomegaly, ↑ GGT, ultrasound)

→ CFTR modulator eligibility assessed

→ CF-related diabetes (CFRD) screening: annual oral glucose tolerance test (OGTT) starting at age 10 — fasting glucose and HbA1c are insensitive for CFRD detection

→ Psychosocial: depression/anxiety rates are 2–3× general population; annual screening recommended

→ Reproductive counseling: males — CBAVD/azoospermia; females — ↓ fertility but pregnancy possible, especially on CFTR modulators

→ Bone density: DEXA scan by late adolescence; risk factors include vitamin D deficiency, chronic inflammation, glucocorticoid use

School-age (6–12 years):

Adolescents:

Board pearl: CFRD has features of both type 1 (insulin deficiency from pancreatic fibrosis) and type 2 (some insulin resistance) — treated with insulin; oral hypoglycemics are not recommended; DKA is rare

Pulmonary Complications — Exacerbations and Acute Events

Pulmonary exacerbations are the primary driver of lung function decline.

→ Anti-pseudomonal regimen: IV tobramycin + anti-pseudomonal beta-lactam (e.g., piperacillin-tazobactam, ceftazidime, meropenem)

→ Combination therapy ↓ resistance emergence

Definition: ↑ cough, ↑ sputum production, ↓ FEV₁, new crackles/wheeze, ↓ exercise tolerance, ↓ appetite, weight loss — no single validated definition

Mild exacerbation: outpatient oral antibiotics targeted to most recent sputum culture (e.g., amoxicillin-clavulanate for H. influenzae, TMP-SMX or dicloxacillin for S. aureus)

Moderate-severe exacerbation → IV antibiotics (typically 14 days):

Board pearl: Aminoglycoside pharmacokinetics differ in CF — ↑ volume of distribution + ↑ renal clearance → CF patients require HIGHER mg/kg doses and extended-interval (once-daily) dosing with peak/trough monitoring

Hemoptysis: minor (<5 mL) is common; massive (>240 mL/24h or recurrent >100 mL/day) → hold airway clearance, hold inhaled hypertonic saline/dornase, bronchial artery embolization

Pneumothorax: ↑ risk in advanced disease; chest tube drainage; pleurodesis for recurrence (may complicate future lung transplant candidacy)

Gastrointestinal and Hepatobiliary Complications

GI involvement is the second major disease axis after pulmonary disease.

→ PERT: lipase-based dosing — infants: 2,000–4,000 units lipase per 120 mL formula/breastfeed; children: 500–2,500 units lipase/kg/meal, max 10,000 units lipase/kg/day

→ Board pearl: Doses >6,000 units lipase/kg/meal are associated with fibrosing colonopathy — a stricturing complication of the ascending colon

Pancreatic insufficiency (~85%): malabsorption of fat + fat-soluble vitamins → steatorrhea, failure to thrive

Distal intestinal obstruction syndrome (DIOS): acute/subacute obstruction in ileocecum from inspissated stool + mucus; treat with oral/rectal osmotic agents (PEG, Gastrografin); distinguish from constipation (gradual, non-acute)

CF-related liver disease: focal biliary cirrhosis → multilobular cirrhosis → portal hypertension; ursodeoxycholic acid sometimes used; monitor with US + LFTs

Pancreatitis: paradoxically occurs in pancreatic-sufficient CF patients (~15%) who retain enough function to generate enzymes

GERD: highly prevalent → contributes to pulmonary disease via microaspiration

Clinical tip: If a CF child has worsening steatorrhea despite adequate PERT doses → check compliance, consider ↑ gastric acid (add PPI to ↑ duodenal pH for enzyme activation), or evaluate for DIOS/bacterial overgrowth

Key Differentials — Chronic Cough and Failure to Thrive in Infants

Several conditions mimic CF; distinguishing features help narrow the differential.

Primary ciliary dyskinesia (PCD): autosomal recessive; chronic wet cough, sinusitis, bronchiectasis — similar to CF but sweat Cl⁻ is NORMAL; ~50% have situs inversus; nasal nitric oxide is LOW; diagnosed by ciliary biopsy/electron microscopy or genetic testing

Immunodeficiency (e.g., common variable immunodeficiency, specific antibody deficiency): recurrent sinopulmonary infections + bronchiectasis but no malabsorption; evaluate with immunoglobulins + vaccine titers

Allergic bronchopulmonary aspergillosis (ABPA): occurs IN CF patients (8–15%) → suspect when ↑ total IgE (>500 IU/mL), Aspergillus-specific IgE/IgG, new infiltrates, ↓ FEV₁; treat with corticosteroids + antifungals

Celiac disease / cow's milk protein intolerance: failure to thrive + diarrhea, but no chronic respiratory symptoms; sweat Cl⁻ normal

Shwachman-Diamond syndrome: exocrine pancreatic insufficiency + neutropenia + skeletal anomalies — no lung disease initially; sweat Cl⁻ normal

Board pearl: Nasal polyps in a child <12 years → sweat test to rule out CF; nasal polyps in a teen → more likely allergic rhinitis, but CF should still be considered

Key Differentials — Wheezing and Bronchiectasis in Older Children

→ Key distinction: Asthma is episodic with symptom-free intervals and good bronchodilator response; CF has persistent daily symptoms and progressive structural lung disease

Asthma vs. CF: both cause cough + wheeze; CF has chronic productive cough, digital clubbing, failure to thrive, Pseudomonas in sputum — features atypical for asthma

Non-CF bronchiectasis: can result from recurrent aspiration (neuromuscular disease, tracheoesophageal fistula), post-infectious (adenovirus, pertussis, TB), immunodeficiency, PCD, or foreign body

Tracheomalacia/bronchomalacia: presents with chronic cough and wheeze; diagnosis by dynamic airway evaluation (flexible bronchoscopy or dynamic CT)

Aspiration syndromes: recurrent pneumonia in dependent lung zones; history of feeding difficulties, GERD, or neurologic impairment

Protracted bacterial bronchitis (PBB): chronic wet cough >4 weeks in otherwise healthy child; resolves with 2–4 weeks of oral antibiotics; if recurrent → evaluate for underlying cause including CF

Clinical tip: Any child with chronic productive cough + failure to thrive OR recurrent lower respiratory infections warrants a sweat test regardless of NBS result (NBS has a ~5% false-negative rate depending on protocol)

Preventive Care — Routine Monitoring and Screening Schedules

CF care is best delivered at CF Foundation–accredited centers with quarterly multidisciplinary visits.

→ Weight, height, BMI percentile

→ Respiratory culture (oropharyngeal swab or expectorated sputum)

→ Spirometry (≥6 years): FEV₁, FVC, FEF₂₅₋₇₅

→ Symptom review + airway clearance technique check

→ Fat-soluble vitamin levels (A, D, E, prothrombin time for vitamin K status)

→ Liver function tests (AST, ALT, GGT)

→ Fasting glucose or 2-hour OGTT (starting at age 10 for CFRD screening)

→ Chest radiograph (some centers use CT periodically to detect early bronchiectasis)

Every visit (quarterly):

Annually:

Every 1–3 years: bone density (DEXA) in adolescents/adults, abdominal ultrasound for liver disease

Board pearl: OGTT is the recommended CFRD screening tool — HbA1c and fasting glucose miss early CFRD because post-prandial insulin deficiency occurs first

Vaccinations: standard childhood schedule + annual influenza + pneumococcal vaccines; COVID-19 vaccination emphasized; CF patients should NOT receive live intranasal influenza vaccine

Preventive Care — Infection Control and Anticipatory Guidance

Infection prevention is critical — patient-to-patient transmission of resistant organisms can be devastating.

→ Rationale: epidemic strains of Pseudomonas and Burkholderia can transmit between CF patients

CF patients should NOT be in close contact with other CF patients (≥6 feet apart); separate clinic rooms, no shared equipment

Hand hygiene: meticulous; nebulizer equipment must be cleaned and disinfected after every use

Environmental counseling: avoid standing water, hot tubs, gardening soil/compost (sources of Pseudomonas, nontuberculous mycobacteria, Aspergillus)

Smoke exposure: absolute avoidance — secondhand smoke accelerates lung function decline

Nutrition anticipatory guidance: high-calorie, high-fat diet (120–150% of RDA for calories); salt supplementation especially in hot weather or during exercise

Exercise: strongly encouraged — improves airway clearance, cardiovascular fitness, bone health, and psychosocial well-being

Clinical tip: Educate families that PERT capsules should be given at the BEGINNING of meals/snacks, swallowed whole (or sprinkled on acidic food for young children — not chewed or crushed into alkaline foods that inactivate the enteric coating)

Family Counseling and Psychosocial Considerations

CF imposes an enormous treatment burden — daily therapy time averages 2–4 hours.

→ Use motivational interviewing; simplify regimens when possible; address barriers (time, school, social stigma)

At diagnosis: grief response is common; provide clear, honest information about prognosis while emphasizing dramatic improvements with CFTR modulators

Genetic counseling: autosomal recessive — 25% recurrence risk per pregnancy; carrier testing for extended family; prenatal/preconception options

Treatment adherence: the #1 modifiable factor affecting outcomes; adolescence is the highest-risk period for non-adherence

Mental health: CFF recommends annual screening for depression and anxiety in patients ≥12 years AND caregivers; refer to behavioral health as needed

School/social: 504 plan or IEP for accommodations (extra time for treatments, bathroom access, caloric supplementation)

Transition planning: begin discussing adult CF care transfer by age 12–14; structured transition at age 18–21

Board pearl: Caregiver burnout is a recognized risk factor for poor patient outcomes — always assess parental well-being at visits

End-of-life: palliative care discussions should be introduced early in advanced disease; lung transplant referral when FEV₁ <30% predicted or rapid decline

High-Yield Associations and Rapid-Fire Facts

Most common lethal autosomal recessive disease in Caucasians → CF

Most common mutation → F508del (class II — misfolded protein degraded before reaching cell surface)

Meconium ileus in a newborn → CF until proven otherwise

Nasal polyps in a child <12 years → sweat test

Rectal prolapse in a toddler → sweat test

Pseudo-Bartter syndrome (hyponatremic, hypochloremic metabolic alkalosis with ↑ renin/aldosterone) → CF infant with excessive salt loss

Sweat Cl⁻ ≥60 mmol/L on two occasions → diagnostic

CFRD screening → OGTT annually starting at age 10; NOT HbA1c

Digital clubbing + chronic productive cough + failure to thrive → CF

Most common cause of death → progressive respiratory failure from bronchiectasis

Fibrosing colonopathy → lipase dose >6,000 units/kg/meal

CBAVD → infertility in >95% of CF males

Burkholderia cepacia → poor prognosis, relative transplant contraindication

Aminoglycoside dosing in CF → higher mg/kg due to ↑ Vd and ↑ clearance

ETI (Trikafta) → eligible if ≥1 F508del allele; ≥2 years old; monitor LFTs and ophthalmologic exams

One-Line Recap

Cystic fibrosis is an autosomal recessive CFTR channelopathy (most commonly F508del) diagnosed by newborn screening (↑ IRT) confirmed with sweat chloride ≥60 mmol/L on two occasions; management rests on four pillars — airway clearance (CPT/vest/PEP BID) + mucolytics (dornase alfa, hypertonic saline) + aggressive treatment of chronic infections (anti-pseudomonal inhaled antibiotics, azithromycin) + CFTR modulator therapy (elexacaftor/tezacaftor/ivacaftor for ≥1 F508del allele, ≥2 years) — alongside pancreatic enzyme replacement (500–2,500 units lipase/kg/meal, never >6,000 to avoid fibrosing colonopathy), fat-soluble vitamin supplementation, high-calorie diet, NaCl supplementation, annual CFRD screening by OGTT from age 10, and quarterly multidisciplinary CF center visits tracking FEV₁, respiratory cultures, and nutritional status; key board triggers include meconium ileus, nasal polyps in young children, pseudo-Bartter syndrome, recurrent Pseudomonas in a child, and a normalizing or declining FEV₁ signaling the need for treatment escalation or transplant referral.

Board Question Stem Patterns

Newborn with bilious emesis, abdominal distension, failure to pass meconium → diagnosis → meconium ileus → next step → contrast enema + sweat test after stabilization

NBS shows elevated IRT → next step → sweat chloride test at ≥2 weeks/≥2 kg at accredited center

3-month-old with edema, anemia, hypoalbuminemia → diagnosis → CF with pancreatic insufficiency → next step → sweat test

Infant with hyponatremic, hypochloremic metabolic alkalosis in summer → diagnosis → CF (pseudo-Bartter) → next step → sweat test + NaCl supplementation

5-year-old with CF, new culture grows mucoid Pseudomonas → next step → inhaled tobramycin eradication protocol (28 days on/28 off)

10-year-old with CF, annual screening → best test for CFRD → 2-hour OGTT

CF child with worsening steatorrhea on PERT → next step → verify dose/timing, add PPI, check for DIOS

CF teen with acute RLQ pain + palpable mass → diagnosis → DIOS (not appendicitis) → treat with osmotic lavage

8-year-old with CF, total IgE >1,000, new CXR infiltrate, ↓ FEV₁, peripheral eosinophilia → diagnosis → ABPA → treat with systemic corticosteroids ± itraconazole

CF adolescent with FEV₁ <30% predicted → next step → referral for lung transplant evaluation

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