Respiratory

Cystic fibrosis: adult care and CFTR modulator therapy

Clinical Overview and When to Suspect Cystic Fibrosis in Adults

— Recurrent or unexplained bronchiectasis, especially upper-lobe predominant

— Chronic Pseudomonas aeruginosa, Staphylococcus aureus, or nontuberculous mycobacterial (NTM) airway infection

— Recurrent pancreatitis (often pancreatic-sufficient CFTR variants)

— Congenital bilateral absence of the vas deferens (CBAVD) in a man evaluated for infertility

— Chronic rhinosinusitis with nasal polyps in adulthood

— Unexplained fat-soluble vitamin deficiency, steatorrhea, or failure to thrive

— Hypochloremic, hypokalemic metabolic alkalosis with hyponatremia (pseudo-Bartter)

— Distal intestinal obstruction syndrome (DIOS) or unexplained recurrent SBO

Cystic fibrosis (CF) is an autosomal recessive disease caused by biallelic pathogenic variants in CFTR, encoding a cAMP-regulated chloride/bicarbonate channel on epithelial surfaces.

Loss of CFTR function → viscous airway secretions, mucus plugging, chronic bacterial infection, bronchiectasis, pancreatic insufficiency, CF-related diabetes (CFRD), hepatobiliary disease, infertility, and salt-loss syndromes.

Adult CF demographics have shifted dramatically: with newborn screening (universal in US since 2010) and CFTR modulators, median predicted survival now exceeds 50 years, and >57% of US CF patients are adults. Internists and adult pulmonologists now manage the majority of CF care.

When to suspect CF in an adult who has not been previously diagnosed:

CFTR variant classes I–VI determine residual function and modulator eligibility; F508del is the most common pathogenic variant (≈70% of alleles in US).

Board pearl: A young adult man with azoospermia + chronic sinusitis + bronchiectasis has CF until proven otherwise — order sweat chloride and CFTR genotyping, not just a semen analysis.

Step 3 management: Suspected adult CF → refer to an accredited CF Foundation care center for sweat chloride testing, CFTR sequencing, and multidisciplinary longitudinal care.

Presentation Patterns and Key History

— Chronic productive cough, purulent sputum, recurrent pulmonary exacerbations with increased cough, sputum volume/color change, dyspnea, weight loss, and FEV₁ decline ≥10% from baseline

— Hemoptysis (small or massive), pneumothorax, chronic sinusitis, nasal polyposis

— Colonization sequence: S. aureus (including MRSA) → H. influenzae → P. aeruginosa → Burkholderia cepacia complex, Stenotrophomonas, Achromobacter, NTM (M. abscessus, M. avium), Aspergillus (ABPA)

— Pancreatic insufficiency (~85%) → steatorrhea, ADEK deficiency, low BMI

— CF-related diabetes (CFRD) — distinct from T1DM/T2DM; insulin-deficient with preserved insulin sensitivity initially

— CF liver disease (focal biliary cirrhosis → multilobular cirrhosis, portal hypertension)

— DIOS (RLQ pain, palpable cecal mass, partial obstruction); constipation, GERD, SIBO

— Pancreatitis in pancreatic-sufficient variants (R117H, 3849+10kbC>T)

— Men: >95% infertile due to CBAVD (obstructive azoospermia, normal spermatogenesis)

— Women: reduced fertility from thick cervical mucus; pregnancy increasingly common on modulators

— Modulator adherence and side effects (LFTs, mood, cataracts in pediatric carryover)

— Airway clearance routine (frequency, technique, dornase alfa, hypertonic saline)

— Sputum culture history including NTM and resistance patterns

— Exacerbation frequency, last IV antibiotic course, vascular access history

— Reproductive plans, contraception, mental health screening

Pulmonary domain (dominant cause of morbidity/mortality):

GI/nutrition domain:

Genitourinary/reproductive:

MSK/endocrine: CF bone disease (osteopenia, fragility fractures), hypertrophic osteoarthropathy, delayed puberty

Key history to elicit on every adult CF visit:

Board pearl: New glucose intolerance in a CF adult mandates annual OGTT screening starting at age 10; HbA1c is insensitive and not used to diagnose CFRD.

Physical Exam Findings and Multisystem Assessment

— Low BMI historically, but modulator-era weight gain can now produce overweight/obese CF adults — recalibrate nutrition counseling accordingly

— Digital clubbing (chronic hypoxemia/bronchiectasis), cyanosis in advanced disease

— Salty taste to skin (parental report); hyperpigmentation with adrenal insufficiency from chronic steroids

— Nasal polyps, mucopurulent rhinorrhea, frontal/maxillary sinus tenderness

— Dental enamel defects, halitosis

— Coarse crackles, especially upper lobes; expiratory wheeze; prolonged expiration

— Increased AP diameter, accessory muscle use in advanced disease

— Auscultate for localized rhonchi suggesting mucus plug (consider bronchoscopy if persistent)

— Assess SpO₂ at rest and with ambulation; nocturnal desaturation common

— Loud P2, RV heave, TR murmur, elevated JVP → cor pulmonale from chronic hypoxic pulmonary hypertension

— RLQ fullness or mass suggesting DIOS; hepatomegaly, splenomegaly, caput medusae in CF liver disease with portal hypertension

— Surgical scars (meconium ileus repair, prior bowel resections)

— Tachycardia, tachypnea, accessory muscle use, paradoxical abdominal motion → impending respiratory failure

— Volume status — patients often salt- and volume-depleted (sweat losses, poor intake), with risk of pseudo-Bartter

General/nutrition:

HEENT:

Pulmonary:

Cardiac:

Abdominal:

MSK: Kyphosis, vertebral compression tenderness (CF bone disease); HPOA with painful wrist/ankle periostitis

Skin: Easy bruising (vitamin K deficiency), aquagenic wrinkling of palms (a CF-associated sign)

Hemodynamic assessment in exacerbation:

Key distinction: Crackles in CF are typically chronic and upper-lobe predominant, unlike the basilar crackles of CHF or idiopathic pulmonary fibrosis — anatomic predilection reflects mucus stasis and bronchiectasis distribution, a high-yield exam discriminator.

Diagnostic Workup — Initial Labs, Imaging, and Microbiology

— Sweat chloride test (pilocarpine iontophoresis, gold standard):

— ≥60 mmol/L = diagnostic

— 30–59 mmol/L = intermediate, requires CFTR genotyping/extended testing

— <30 mmol/L = CF unlikely (use ≤29 in adults per CFF 2017 guidelines)

— CFTR gene sequencing if sweat chloride intermediate or atypical phenotype; identify two pathogenic variants in trans

— Nasal potential difference (NPD) or intestinal current measurement at specialized centers for diagnostic uncertainty

— CBC, CMP (LFTs, glucose, creatinine), fat-soluble vitamins A, D, E, K (INR as surrogate), HbA1c is unreliable — use annual 2-hour 75g OGTT starting at age 10 for CFRD screening

— Fecal elastase-1 <100 µg/g confirms pancreatic insufficiency

— IgE total and Aspergillus-specific IgE/IgG, eosinophil count if ABPA suspected

— 25-OH vitamin D, DEXA scan baseline at age 18 then every 1–5 years

— Chest CT (high-res) — upper-lobe bronchiectasis, mucus plugging, tree-in-bud, cysts, atelectasis; baseline then as clinically indicated

— CXR for acute exacerbation, suspected pneumothorax, or hemoptysis

— Sinus CT for chronic refractory sinusitis preoperatively

— Sputum culture every clinic visit (≥quarterly) with susceptibilities; specific NTM culture at least annually (decontaminated with NALC-NaOH or oxalic acid)

— Screen for MRSA, Pseudomonas, Burkholderia, Stenotrophomonas, Achromobacter, fungi

— Spirometry every clinic visit; FEV₁ % predicted is the central longitudinal monitor

Confirming the diagnosis (adult presentation):

Baseline and routine adult labs:

Imaging:

Microbiology — cornerstone of CF care:

Pulmonary function:

Board pearl: A normal sweat chloride does not exclude CF in patients with certain residual-function variants (e.g., 3849+10kbC>T, R117H-7T). Always pair sweat testing with CFTR genotyping when clinical suspicion is high.

Diagnostic Workup — Advanced and Confirmatory Studies

— Initial panel screens common variants; if only one or zero variants found with strong phenotype, proceed to full CFTR sequencing + deletion/duplication analysis

— Variant classification per CFTR2 database (clinvar-linked) drives modulator eligibility — critical because FDA labels are variant-specific

— Variant classes:

— Class I — nonsense/no protein (e.g., G542X)

— Class II — misfolding/trafficking (F508del)

— Class III — gating defect (G551D)

— Class IV — conductance defect (R117H)

— Class V — reduced synthesis (3849+10kbC>T)

— Class VI — reduced stability at membrane

— 6-minute walk test with continuous oximetry for exertional desaturation

— Cardiopulmonary exercise test (CPET) — VO₂ max prognostic and pre-transplant

— Lung clearance index (LCI) — sensitive for early small-airway disease, used research/pediatric

— Bronchoscopy with BAL for non-expectorating patients or refractory exacerbations

— HRCT for bronchiectasis quantification, NTM disease, ABPA mucus plugging (high-attenuation mucus)

— Liver elastography (FibroScan) annually for CF liver disease surveillance

— Abdominal US with Doppler if portal hypertension suspected

— MRCP for suspected CF-related biliary disease or recurrent pancreatitis

— DEXA + vertebral fracture assessment; testosterone in hypogonadal men

— OGTT annually for CFRD; continuous glucose monitoring increasingly used

— Men with CBAVD → scrotal US, semen analysis, FSH/testosterone; sperm retrieval (TESE) + ICSI for fertility

CFTR genotyping logistics:

Pulmonary advanced testing:

GI/hepatic workup:

Bone/endocrine:

Reproductive evaluation:

Step 3 management: Once CF is confirmed, all patients should be enrolled in a CF Foundation–accredited center for longitudinal, multidisciplinary care; outcomes (FEV₁, BMI, survival) are demonstrably better at accredited centers — a board-tested health systems point.

Risk Stratification and Management Framework

— FEV₁ % predicted — central longitudinal metric; FEV₁ <30% historically marked transplant evaluation, though modulator era has shifted thresholds

— BMI — strong independent predictor of FEV₁ and survival; target BMI ≥22 (women) and ≥23 (men)

— Exacerbation frequency — ≥2/year predicts accelerated FEV₁ decline

— Chronic infection profile — B. cepacia complex, M. abscessus portend worse outcomes

— Comorbidities — CFRD, CF liver disease with portal hypertension, pulmonary hypertension

1. Airway clearance — high-frequency chest wall oscillation vest, PEP devices, autogenic drainage, daily

2. Inhaled therapies — dornase alfa daily, hypertonic saline 7% BID, inhaled antibiotics for chronic Pseudomonas

3. CFTR modulators — variant-directed (see chunk 7)

4. Nutrition + pancreatic enzyme replacement (PERT) — high-calorie, high-fat diet; ADEK supplementation; salt supplementation

— Mild → oral antibiotics targeted to recent culture, intensified airway clearance

— Moderate/severe → IV antibiotics × 14 days (often 2-drug anti-pseudomonal), inpatient or home infusion

Severity is multidimensional in CF — no single score dominates:

Four pillars of chronic CF care (the "every clinic visit" framework):

Quarterly CF clinic visits with: spirometry, sputum culture, weight/BMI, modulator adherence, mental health screen (PHQ-9 and GAD-7 annually, per CFF/ECFS guidelines)

Annual battery: OGTT, fat-soluble vitamins, LFTs, CBC, sputum NTM, chest imaging as indicated, DEXA per schedule

Pulmonary exacerbation definition: clinical — increased cough/sputum, dyspnea, weight loss, ≥10% FEV₁ drop, new CXR findings, hemoptysis, fever — at least 2–3 features

Treatment intensity ladder for exacerbations:

CCS pearl: For a moderate CF exacerbation, the initial CCS orders are: admit, continuous pulse ox, sputum culture + sensitivities, CBC/CMP/CRP, CXR, IV anti-pseudomonal β-lactam + IV aminoglycoside or fluoroquinolone, chest physiotherapy q4h, nebulized bronchodilator + hypertonic saline, continue home modulator therapy, nutrition consult, and CF center pulmonology consult.

Pharmacotherapy — CFTR Modulators (First-Line Disease-Modifying Therapy)

— Potentiators (open the channel at the membrane) — ivacaftor

— Correctors (rescue folding/trafficking) — lumacaftor, tezacaftor, elexacaftor

— Ivacaftor (Kalydeco) — monotherapy for gating variants (G551D and others) and selected residual-function variants; age ≥1 month

— Lumacaftor/ivacaftor (Orkambi) — F508del homozygotes; largely superseded

— Tezacaftor/ivacaftor (Symdeko) — F508del homozygotes + select residual-function variants

— Elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta/Kaftrio) — first-line for ≥1 F508del allele OR any responsive variant per expanded FDA label; age ≥2 years

— +14 percentage points FEV₁, ~63% reduction in exacerbations, weight gain, reduced sweat chloride, improved quality of life, declining lung transplant referrals

— Hepatotoxicity — check LFTs at baseline, then q3 months × 1 year, then annually; hold for ALT/AST >5× ULN or >3× ULN with bilirubin >2× ULN

— Cataracts — baseline and annual ophthalmologic exam (especially in pediatrics, but continue in adults)

— Drug interactions — CYP3A4 substrates; strong inducers (rifampin, phenytoin, St. John's wort) contraindicated; strong inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir) require dose reduction

— Mental health effects — depression, anxiety, insomnia, "brain fog" reported; screen with PHQ-9/GAD-7 before and during therapy

— Rash, headache, elevated CK, hypertension (with ETI)

CFTR modulators are the paradigm-shifting therapy of the past decade — they target the underlying protein defect rather than downstream consequences.

Two mechanistic classes:

Currently approved regimens (US, 2024):

Eligibility is variant-specific — must confirm CFTR genotype against current FDA label/CFTR2 database before prescribing.

Clinical impact of ETI (landmark trials):

Key adverse effects and monitoring (Step 3 high-yield):

Board pearl: Before prescribing elexacaftor/tezacaftor/ivacaftor, verify the CFTR genotype, baseline LFTs, ophthalmologic exam (if pediatric or symptomatic), and review medication list for CYP3A4 interactions — these are the most commonly tested management points.

Adjunctive Pharmacotherapy and Procedural Management

— Dornase alfa (recombinant DNase) nebulized once daily — cleaves neutrophil DNA in mucus; improves FEV₁, reduces exacerbations

— Hypertonic saline 7% BID — osmotic mucus hydration; pretreat with bronchodilator

— Mannitol dry powder — alternative osmotic agent

— Tobramycin inhalation solution (TIS) or tobramycin powder — 28 days on / 28 days off

— Aztreonam lysine inhaled — alternate-month cycling

— Colistin inhaled — second-line

— Two-drug anti-pseudomonal regimen × 14 days: anti-pseudomonal β-lactam (piperacillin-tazobactam, cefepime, ceftazidime, meropenem) + aminoglycoside (tobramycin) or fluoroquinolone

— Dose aminoglycosides by extended-interval CF protocols; monitor levels, audiology, renal function

— Cover MRSA (vancomycin/linezolid) if cultured

— B. cepacia and M. abscessus require ID consultation and prolonged combination therapy

— Azithromycin 250–500 mg three times weekly — immunomodulatory; reduces exacerbations in chronic Pseudomonas; screen for NTM first (azithromycin monotherapy can induce macrolide resistance in NTM)

— High-dose ibuprofen in pediatrics (rarely in adults)

— Bronchoscopy for refractory mucus plugging, hemoptysis evaluation

— Bronchial artery embolization for massive hemoptysis (>240 mL/24h or recurrent)

— Chest tube/pleurodesis for recurrent pneumothorax (avoid surgical pleurodesis if transplant candidate — relative not absolute contraindication today)

— Lung transplantation — bilateral; criteria include FEV₁ <30%, rapid decline, recurrent ICU exacerbations, PaCO₂ rise, pulmonary hypertension

— Liver transplantation for decompensated CF cirrhosis; combined lung-liver in selected cases

Inhaled therapies (daily chronic):

Inhaled antibiotics for chronic Pseudomonas infection:

Pulmonary exacerbation IV antibiotics:

ABPA: oral prednisone + itraconazole/voriconazole (with modulator interaction adjustment); consider omalizumab/dupilumab in select cases

Anti-inflammatory adjuncts:

Pancreatic enzyme replacement (PERT): lipase 500–2,500 units/kg/meal; titrate to symptoms; avoid >10,000 units/kg/day (fibrosing colonopathy)

Procedural and surgical management:

Step 3 management: For massive hemoptysis in CF → secure airway with bleeding side down, hold NSAIDs/inhaled tobramycin/hypertonic saline, urgent bronchial artery embolization.

Special Populations — Elderly, Renal, and Hepatic Impairment

— Cumulative aminoglycoside exposure → ototoxicity (high-frequency hearing loss, vestibular dysfunction) and nephrotoxicity — audiometry annually in chronically treated patients

— Increased risk of colorectal cancer — CFF recommends colonoscopy starting at age 40, repeat every 5 years (every 3 years after first polyp); post-transplant patients screen at 30 — a high-yield distinction from average-risk USPSTF guidance

— Cardiovascular disease emerging as patients live longer; lipid screening, BP control

— Polypharmacy and drug interactions (especially with modulator CYP3A4 sensitivity)

— Osteoporosis — DEXA every 1–5 years; bisphosphonates if T-score ≤ −2.0 or fragility fracture; address vitamin D, calcium, hypogonadism

— Adjust aminoglycosides by levels and creatinine clearance; tobramycin trough <1 µg/mL, peak 20–40 with extended-interval

— Vancomycin — AUC-guided dosing (400–600 mg·h/L)

— Colistin nephrotoxic — monitor closely

— Modulators — no dose adjustment for mild/moderate CKD; avoid or reduce in severe (eGFR <30) and ESRD per label caution

— Post-lung transplant CKD common from calcineurin inhibitors — coordinate care

— CF liver disease ranges from elevated LFTs to multilobular cirrhosis with portal hypertension and varices

— Ursodeoxycholic acid historically used; evidence weak, no clear mortality benefit

— Modulator dosing in hepatic impairment:

— Mild (Child-Pugh A) — no adjustment

— Moderate (Child-Pugh B) — reduced dose (e.g., ETI: one orange tablet daily instead of two)

— Severe (Child-Pugh C) — use only if benefit outweighs risk; reduced dose with close monitoring

— Variceal screening per AASLD; avoid hepatotoxic concomitants

The "elderly" CF patient is a new phenomenon — modulator-era adults are reaching their 60s–70s with disease trajectories no prior generation experienced.

Aging-related considerations:

Renal impairment:

Hepatic impairment:

Board pearl: A CF adult with cirrhosis on elexacaftor/tezacaftor/ivacaftor who develops worsening LFTs needs the modulator held, not just dose-reduced, until ALT/AST/bilirubin stabilize — then reintroduced cautiously per CFF guidance.

Special Populations — Pregnancy, Fertility, and Reproductive Care

— Partner CFTR carrier screening — 1 in 25 White Americans are carriers; if partner is carrier, 50% offspring risk of CF; offer preimplantation genetic testing or prenatal diagnosis (CVS at 10–13 wk, amnio at 15–20 wk)

— Optimize FEV₁ (ideally >50–60% predicted), BMI, CFRD control (HbA1c goal <6.5%), eradicate active infections

— Review modulator continuation — generally continued through pregnancy based on observational data showing maternal benefit and no clear fetal harm; shared decision-making documented

— Update vaccines (Tdap, influenza, COVID-19, RSV per pregnancy guidance)

— Folate, prenatal vitamins (CF-specific high-dose ADEK)

— Co-management by MFM + CF center pulmonology

— Spirometry each trimester; sputum culture; OGTT at 12–16 weeks and again 24–28 weeks (CFRD risk)

— Nutrition surveillance — weight gain often inadequate

— Avoid contraindicated CF meds: aminoglycosides (ototoxicity), tetracyclines, fluoroquinolones generally avoided, voriconazole (teratogenic)

— Modulators excreted in breast milk at low levels; breastfeeding considered compatible with shared decision-making and infant LFT monitoring

— Vaginal delivery preferred unless obstetric indication; regional anesthesia favored

— Postpartum exacerbation common — proactive airway clearance, follow-up within 1–2 weeks

— CBAVD in >95% — obstructive azoospermia with normal spermatogenesis

— Fertility via microsurgical epididymal/testicular sperm extraction + ICSI

— All methods generally acceptable; consider LARC (IUDs, implants)

— Modulator-induced increased fertility may surprise patients — explicitly counsel

The modulator era has dramatically increased fertility and pregnancy in women with CF — pregnancy rates have more than doubled since ETI approval.

Preconception counseling (Step 3 ambulatory cornerstone):

Antepartum management:

Delivery:

Male fertility:

Contraception:

Step 3 management: A 28-year-old woman with CF on ETI presents with positive home pregnancy test — order dating ultrasound, CBC, CMP, OGTT now and at 24–28 wk, sputum culture, FEV₁, CFTR partner testing, refer MFM, continue ETI with shared decision-making, and update vaccinations.

Complications and Adverse Outcomes

— Pulmonary exacerbations — leading cause of FEV₁ decline; cumulative exacerbations reduce long-term lung function

— Massive hemoptysis — bronchial artery hypertrophy; mortality ~10%; emergent embolization

— Pneumothorax — apical bleb rupture; chest tube; consider VATS pleurodesis if recurrent (transplant implications)

— Allergic bronchopulmonary aspergillosis (ABPA) — diagnostic criteria: clinical deterioration, total IgE >1,000 IU/mL, Aspergillus-specific IgE, eosinophilia, central bronchiectasis, fleeting infiltrates

— NTM disease — M. avium complex, M. abscessus; difficult to eradicate; impacts transplant candidacy

— Chronic respiratory failure, cor pulmonale, pulmonary hypertension

— DIOS — fecal impaction at ileocecum; treat with PEG, Gastrografin enema, hydration; avoid laparotomy if possible

— CF-related cirrhosis with portal hypertension — varices, splenomegaly, hypersplenism

— Pancreatitis in pancreatic-sufficient variants

— Increased GI malignancy risk — colorectal cancer (5–10× general population), pancreatic, biliary, small bowel

— CFRD — distinct entity; insulin is treatment of choice; avoid carbohydrate restriction (caloric needs remain high)

— CF bone disease — osteopenia/osteoporosis, vertebral fractures, kyphosis

— Hypogonadism, delayed puberty

— Pseudo-Bartter syndrome — hyponatremic, hypokalemic, hypochloremic metabolic alkalosis from sweat salt loss; especially in summer/exercise

— Nephrolithiasis — hyperoxaluria from fat malabsorption

— Aminoglycoside nephrotoxicity cumulative

— Depression and anxiety — 2–3× general population; PHQ-9/GAD-7 annually

— Hearing loss and tinnitus — aminoglycoside-related; consider mitochondrial mutation (m.1555A>G) screening

— Venous access complications — chronic IV antibiotic use; PICC/port thromboses

Pulmonary complications:

GI/hepatobiliary:

Endocrine/metabolic:

Renal/electrolyte:

Other:

Key distinction: CFRD is not type 1 (no autoimmunity, retained C-peptide initially) or type 2 (insulin sensitivity preserved) diabetes — it is insulin deficiency from pancreatic fibrosis. Treatment is insulin only; oral agents are not first-line, and DKA is rare.

When to Escalate — ICU, Consults, and Inpatient Triage

— Pulmonary exacerbation not responsive to outpatient oral antibiotics after 5–7 days

— Need for IV antibiotics when home infusion not feasible or first-time course

— FEV₁ drop >15–20% from baseline

— Hemoptysis >100 mL/24h or recurrent

— Pneumothorax of any size

— Severe DIOS not resolving with oral therapy

— New respiratory failure — hypoxia requiring increased O₂, hypercapnia, accessory muscle use

— Pregnancy + exacerbation, severe CFRD with DKA-like presentation (rare), variceal bleeding

— Respiratory failure requiring NIV or high-flow that is escalating

— Massive hemoptysis (>240 mL/24h or hemodynamic instability)

— Tension pneumothorax or large pneumothorax with respiratory compromise

— Sepsis from CF lung disease or line infection

— Hemodynamic instability, refractory hypoxemia

— NIV preferred bridge for hypercapnic respiratory failure; particularly useful in transplant candidates to avoid intubation

— Avoid prolonged intubation when possible — historically worse outcomes, though ECMO bridging to transplant is increasingly successful in modern centers

— CF Foundation–accredited center pulmonology (call early — outcomes data favor accredited care)

— Infectious disease for B. cepacia, M. abscessus, multidrug-resistant Pseudomonas

— Interventional radiology for hemoptysis embolization or vascular access

— Thoracic surgery for pneumothorax, transplant evaluation

— GI/hepatology for variceal bleeding, decompensated cirrhosis

— Endocrinology for difficult CFRD

— Nutrition, social work, pharmacy, respiratory therapy, mental health — multidisciplinary core

— FEV₁ <30% predicted or rapid decline

— ≥2 exacerbations/year requiring IV antibiotics

— One ICU admission for respiratory failure

— Pulmonary hypertension, hypercapnia, increasing oxygen requirement

Indications for inpatient admission:

ICU triage criteria:

NIV/HFNC role:

Consults to mobilize:

Transplant referral triggers (consider listing thresholds):

CCS pearl: For CF patient with massive hemoptysis in the CCS scenario: upright positioning with bleeding lung dependent, large-bore IV access, type and crossmatch, hold NSAIDs/inhaled tobramycin/hypertonic saline/airway clearance, IV tranexamic acid, urgent bronchial artery embolization consult, ICU admission.

Key Differentials — Same-Category (Other Causes of Bronchiectasis)

— Autosomal recessive; ciliary structural/functional defects

— Triad of chronic sinusitis, bronchiectasis (lower-lobe predominant), and infertility

— Situs inversus in ~50% (Kartagener syndrome)

— Diagnosis: nasal nitric oxide (low), ciliary biopsy with electron microscopy, genetic testing

— Sweat chloride normal; CFTR genotyping negative

— Recurrent sinopulmonary infections, bronchiectasis (often lower lobe)

— Low IgG, IgA, +/− IgM; poor vaccine response

— Treatment with IVIG

— Lower-lobe panacinar emphysema more typical, but can cause bronchiectasis

— Low serum AAT level, ZZ or SZ genotype

— Can occur in or out of CF; central bronchiectasis, high IgE, eosinophilia

— "Lady Windermere" — RML/lingula bronchiectasis, nodular pattern, older nonsmoking women

— Can complicate CF or arise independently

— Childhood pertussis, measles, severe pneumonia, TB sequelae

— Diagnosis of exclusion after workup; up to 40% of adult bronchiectasis

— Rheumatoid arthritis, Sjögren syndrome, IBD-associated

— Lymphedema + yellow dystrophic nails + bronchiectasis/pleural effusions

— CBC with diff, immunoglobulins (IgG, IgA, IgM, IgE), CFTR analysis + sweat chloride, AAT level, RF/anti-CCP/ANA, sputum bacterial + AFB + fungal, HIV, ABPA workup, consider PCD evaluation

Bronchiectasis is the radiographic hallmark of CF, but is etiologically heterogeneous — Step 3 stems often hinge on distinguishing CF from these mimics.

Primary ciliary dyskinesia (PCD):

Common variable immunodeficiency (CVID) and other humoral immunodeficiencies:

Alpha-1 antitrypsin deficiency:

Allergic bronchopulmonary aspergillosis (ABPA):

NTM lung disease (M. avium, M. abscessus):

Post-infectious bronchiectasis:

Idiopathic/cryptogenic bronchiectasis:

Rheumatologic associations:

Yellow nail syndrome:

Diagnostic algorithm for new adult bronchiectasis (BTS/ATS):

Key distinction: Upper-lobe bronchiectasis + pancreatic insufficiency + male infertility = CF. Lower-lobe bronchiectasis + situs inversus + infertility = PCD. Lower-lobe bronchiectasis + hypogammaglobulinemia + recurrent sinopulmonary infections = CVID. Memorize these triads.

Key Differentials — Other-Category Mimics

— Adult smoker with chronic productive cough and obstructive spirometry — typically lower-lobe emphysema or normal CT; no bronchiectasis predominance

— CF can be misdiagnosed as early-onset COPD in nonsmoking young adults — order sweat chloride if obstruction is unexplained

— In adults, bilateral nasal polyposis should always prompt consideration of CF (and aspirin-exacerbated respiratory disease, AERD)

— Chronic pancreatitis (alcohol, hereditary, autoimmune)

— Pancreatic cancer

— Shwachman-Diamond syndrome (pancreatic insufficiency + neutropenia + skeletal abnormalities in pediatrics; rarely adult presentation)

— Celiac disease — fat malabsorption pattern but with villous atrophy; tTG-IgA

— Hereditary pancreatitis (PRSS1, SPINK1) — overlap with CFTR

— Alcohol, gallstones, hypertriglyceridemia, hypercalcemia, autoimmune pancreatitis

— Isolated CBAVD without classic CF — most carry at least one CFTR variant (often R117H, 5T allele); evaluate as a CF-spectrum disorder

— Klinefelter syndrome (47,XXY) — small firm testes, gynecomastia, elevated FSH/LH

— Y-chromosome microdeletions

— True Bartter syndrome — genetic tubulopathy, typically presents in childhood with growth failure; hypercalciuria

— Gitelman syndrome — hypocalciuria, hypomagnesemia

— Diuretic abuse, surreptitious vomiting

— TB, malignancy, vasculitis (GPA, anti-GBM), AVM, mitral stenosis, PE with infarct

— IBD (Crohn especially), eating disorders, hyperthyroidism, occult malignancy, HIV

COPD/asthma overlap:

Chronic rhinosinusitis with nasal polyposis:

Pancreatic insufficiency differential:

Recurrent pancreatitis differential:

Male infertility/CBAVD differential:

Salt-loss/pseudo-Bartter mimics:

Hemoptysis differential:

Failure to thrive in young adults:

Board pearl: A young adult man with recurrent idiopathic pancreatitis + male infertility but normal sweat chloride may have a CFTR-related disorder (formerly "atypical CF") — order full CFTR sequencing; he may still benefit from a modulator if a responsive variant is identified.

Secondary Prevention, Discharge Planning, and Long-Term Care

— Complete 14-day IV antibiotic course (home infusion if stable); arrange PICC care, weekly labs (CBC, BMP, drug levels)

— Audiology + renal function monitoring if aminoglycoside use prolonged or repeated

— Resume modulator therapy (confirm no interaction with discharge antibiotics)

— Optimize airway clearance — vest, dornase alfa, hypertonic saline, inhaled antibiotics on schedule

— Bronchodilator + albuterol PRN

— Pancreatic enzyme replacement dose review

— ADEK vitamins, salt supplementation in summer

— Insulin regimen reconciliation for CFRD

— Mental health follow-up if new diagnosis or symptoms during admission

— CF center clinic visit within 1–2 weeks post-discharge

— Annual influenza (inactivated)

— COVID-19 per current schedule

— PCV20 (or PCV15 → PPSV23 sequence) for all adults with chronic lung disease

— RSV vaccine per current recommendation for CF as chronic lung disease

— Tdap, HPV, MMR, varicella, zoster (age-appropriate, but live vaccines contraindicated post-transplant)

— Hepatitis A and B (especially with CF liver disease)

— Avoid contact with other CF patients (cross-infection risk — Burkholderia, Pseudomonas, M. abscessus)

— Hot tub avoidance (M. avium exposure), proper nebulizer disinfection

— Colonoscopy at age 40 (every 5 years; every 3 years after first polyp); age 30 post-transplant

— Cervical, breast cancer screening per USPSTF; consider HPV-related cancers post-transplant

— BP, lipid screening as patients age; standard ASCVD prevention with attention to drug interactions

— Vitamin D, calcium, bisphosphonate per DEXA results

Discharge from a pulmonary exacerbation admission — Step 3 checklist:

Vaccinations (high-yield, often forgotten):

Chronic infection control:

Cancer screening adjustments:

Cardiovascular and metabolic prevention:

Step 3 management: A CF adult discharging on home tobramycin IV needs scheduled weekly CBC, BMP, tobramycin trough, audiology screening every 3–6 months with chronic exposure, and CF clinic follow-up within 1–2 weeks — these are the ambulatory transition-of-care points commonly tested.

Follow-Up, Monitoring, Rehab, and Counseling

— Spirometry at each visit

— Sputum culture (or oropharyngeal swab if non-productive)

— Weight, BMI, growth trajectory

— Modulator adherence and side effect review

— Airway clearance technique review

— Symptom screen: respiratory, GI, GU, mental health

— Medication reconciliation, drug interaction check

— OGTT (2-hour 75g) for CFRD screening starting age 10

— Fat-soluble vitamins A, D, E, K (INR)

— LFTs, CBC, CMP, lipid panel

— NTM sputum culture

— PHQ-9 and GAD-7 mental health screening (CFF/ECFS guideline)

— Ophthalmology if on modulator (per label)

— Audiology if recurrent aminoglycoside exposure

— DEXA scan (frequency by baseline T-score)

— Chest CT if clinically indicated for bronchiectasis progression, NTM evaluation

— Liver elastography annually, hepatic ultrasound as indicated

— Recommended for FEV₁ <80% or symptomatic; aerobic + resistance training improves exercise tolerance, mucus clearance, QOL

— Daily exercise is itself an airway clearance technique

— Historically high-calorie, high-fat; modulator era shifts emphasis toward balanced macronutrients as patients gain weight and develop cardiometabolic risk

— PERT titration with each meal/snack

— Dietitian visit each clinic visit ideally

— Annual depression/anxiety screening (PHQ-9, GAD-7); refer for therapy/medication as indicated

— Modulator initiation — counsel about possible mood, sleep, cognitive effects; don't stop modulator abruptly without CF center input

— Cascade CFTR testing for siblings and offspring

— Reproductive partner screening

— Pediatric CF center coordination if children

Quarterly CF clinic visit (the longitudinal cadence):

Annual battery:

Every 1–5 years:

Pulmonary rehabilitation:

Nutrition counseling:

Mental health:

Family/genetic counseling:

Board pearl: PHQ-9 ≥10 or GAD-7 ≥10 in a CF adult mandates mental health referral; depression strongly predicts modulator nonadherence and worse pulmonary outcomes — a Step 3 patient-centered care concept.

Ethical, Legal, and Patient Safety Considerations

— ETI (Trikafta) wholesale cost ~$300,000/year — access disparities are significant; some patients require manufacturer patient-assistance programs, Medicaid waivers, or 340B navigation

— Document shared decision-making when cost or insurance limits drive therapy choice

— Health equity: CFTR variants overrepresented in European-ancestry populations have driven modulator development; expanded labels now include rare variants, but patients of African, Asian, and Hispanic ancestry may still have variants not on FDA-responsive lists — advocate for genotype-specific in vitro testing and expanded access

— Preimplantation genetic testing, prenatal diagnosis, and selective termination — provide nondirective counseling

— Fertility preservation discussions before lung transplant or known gonadotoxic exposure

— Pediatric-to-adult CF care transition — formal transition programs starting age 14–16; full handoff by 18–21; abrupt transitions worsen adherence and outcomes

— Post-hospital discharge: 48–72 hour phone follow-up, 1–2 week clinic visit, medication reconciliation including modulator restart

— Strict patient segregation in CF clinics — different appointment rooms/times for patients with Burkholderia, M. abscessus; mask in clinic; no CF camps or in-person CF gatherings

— Mandatory reporting: TB if cultured (often confused with NTM — clarify); not CF itself

— Discuss goals of care, code status, lung transplant preferences before end-stage disease

— Palliative care integration early, not only at end of life — improves symptom burden and mood

— Lung transplant decision-making: candidacy, listing, post-transplant burden

— Many CF adults participate in registries and trials; ensure voluntary, capacity-confirmed consent

— CF Foundation Patient Registry participation — anonymized data drives benchmarking

— Medication reconciliation at every transition — modulators are CYP3A4-sensitive; new prescriptions (e.g., azole antifungal for ABPA) require dose adjustment

— Aminoglycoside cumulative toxicity — track lifetime exposure, audiology, renal function

— Modulator hold for severe hepatotoxicity with structured rechallenge plan

Access and cost:

Reproductive ethics:

Transition of care (a Step 3 favorite):

Infection control:

Advance care planning:

Research and informed consent:

Patient safety pearls:

Step 3 management: When transitioning a 19-year-old from pediatric to adult CF care, the safest practice is a joint transition visit with both teams, formal handoff of medication list (especially modulator and PERT dosing), reproductive counseling, mental health screening, and first adult clinic visit scheduled within 3 months of pediatric discharge.

High-Yield Associations and Rapid-Fire Facts

— Ivacaftor — potentiator (G551D, gating)

— ETI (elexacaftor/tezacaftor/ivacaftor) — corrector-corrector-potentiator for ≥1 F508del

Genetics: Autosomal recessive; CFTR on chromosome 7q31.2; F508del most common variant (~70% alleles US); >2,000 variants described; CFTR2 database curates clinical significance.

Pathophysiology: CFTR is a cAMP-activated Cl⁻ and HCO₃⁻ channel; loss → dehydrated airway surface liquid → impaired mucociliary clearance.

Sweat chloride cutoffs (adults): ≤29 normal, 30–59 intermediate, ≥60 diagnostic.

Pancreatic insufficiency: 85% of CF patients; fecal elastase-1 <100 µg/g.

CFRD: Diagnosed by OGTT (2-h glucose ≥200); insulin-deficient; insulin is first-line therapy; HbA1c insensitive for screening.

Bronchiectasis distribution in CF: Upper-lobe predominant (vs lower-lobe in PCD, CVID, postinfectious).

Pathogens in order of typical age: S. aureus → H. influenzae → P. aeruginosa → Burkholderia cepacia complex → NTM, Aspergillus.

First inhaled antibiotic for new Pseudomonas isolate: Eradication regimen — inhaled tobramycin 28 days (often single course or repeat per protocol).

ABPA criteria: Clinical decline + total IgE >1,000 IU/mL + Aspergillus-specific IgE + central bronchiectasis + eosinophilia + fleeting infiltrates.

Pseudo-Bartter: Hypochloremic, hypokalemic metabolic alkalosis + hyponatremia in CF, often summer.

DIOS treatment: PEG oral + Gastrografin enema; surgery only if perforation.

Modulators:

Monitor on ETI: LFTs (q3 months × 1y, then annually), ophthalmology, BP, mental health.

Drug interactions: CYP3A4 — avoid rifampin, St. John's wort; dose-reduce with strong inhibitors.

Colon cancer screening: Age 40 in CF, every 5 years; age 30 post-transplant.

Mental health screening: PHQ-9 and GAD-7 annually.

Transplant referral: FEV₁ <30%, rapid decline, recurrent exacerbations, ICU admission.

Vaccines: Annual flu, COVID, PCV20, RSV, hep A/B.

Male infertility: >95% from CBAVD; spermatogenesis intact.

Median predicted survival US 2022: >56 years and rising.

CF Foundation–accredited centers: Better outcomes — refer all suspected/confirmed CF.

Board pearl: If the stem mentions "upper-lobe bronchiectasis + nasal polyps + recurrent pancreatitis + azoospermia" in a young adult — diagnosis is CF; next step is sweat chloride before genotyping.

Board Question Stem Patterns

— 24-year-old man with recurrent sinusitis, nasal polyps, chronic productive cough, infertility evaluation showing azoospermia, CT chest with upper-lobe bronchiectasis. Next step: sweat chloride testing; if 30–59, CFTR sequencing.

— 28-year-old with known CF, increased cough, 8% FEV₁ drop, sputum growing mucoid Pseudomonas. Best next step: admit (or home IV antibiotics if stable), IV anti-pseudomonal β-lactam + tobramycin × 14 days, intensify airway clearance, continue modulator.

— 22-year-old F508del/F508del considering ETI. Pre-initiation workup: baseline LFTs, ophthalmology, BP, medication review for CYP3A4 interactions, mental health screen.

— CF adult with 300 mL hemoptysis in 12 hours. Management: ABCs, bleeding-side down, hold inhaled tobramycin/hypertonic saline/NSAIDs, IV tranexamic acid, urgent bronchial artery embolization, ICU admission.

— CF adult with RLQ pain, palpable mass, partial obstruction on KUB. Diagnosis: DIOS. Treatment: PEG/Gastrografin, hydration; surgery only if complete obstruction or perforation.

— CF adult, asymptomatic, age 19, prior normal screening. Best test: annual 2-hour 75g OGTT, not HbA1c.

— 30-year-old woman with CF on ETI tests positive for pregnancy. Management: continue modulator with shared decision-making, MFM + CF co-management, OGTT at 12–16 wk and 24–28 wk, partner CFTR screening, update vaccines.

— 18-year-old graduating from pediatric CF center. Best practice: joint transition visit with adult team, structured handoff of medications, reproductive counseling, first adult visit within 3 months.

— CF adult with declining FEV₁, new wheeze, eosinophilia, IgE 2,400, central bronchiectasis. Diagnosis: ABPA. Treatment: oral prednisone + itraconazole (with modulator interaction adjustment).

— CF teenager after summer camp with weakness, hyponatremia, hypokalemia, metabolic alkalosis. Management: IV NS with KCl, salt supplementation.

Stem 1 — Late diagnosis:

Stem 2 — Pulmonary exacerbation:

Stem 3 — Modulator initiation:

Stem 4 — Hemoptysis:

Stem 5 — DIOS:

Stem 6 — CFRD screening:

Stem 7 — Pregnancy:

Stem 8 — Transition of care:

Stem 9 — ABPA:

Stem 10 — Pseudo-Bartter:

Step 3 management pattern: Stems often test the next monitoring action (LFTs at 3 months on ETI, OGTT annually, colonoscopy at 40, audiology with chronic tobramycin) — memorize the interval schedule, not just initiation.

One-Line Recap

Cystic fibrosis in the adult is a multisystem CFTR channelopathy whose modern care centers on CFTR-variant-directed modulator therapy (elexacaftor/tezacaftor/ivacaftor for ≥1 F508del) layered on top of lifelong airway clearance, inhaled mucolytics and antibiotics, pancreatic enzyme replacement, CFRD insulin therapy, vigilant infection surveillance, mental health and reproductive care, all delivered through a CF Foundation–accredited multidisciplinary center.

Diagnosis pillars: Sweat chloride ≥60 mmol/L + two pathogenic CFTR variants + compatible clinical phenotype; in adults, suspect with upper-lobe bronchiectasis, chronic Pseudomonas, CBAVD-related infertility, nasal polyposis, or recurrent pancreatitis.

Treatment pillars: CFTR modulators (genotype-directed), daily airway clearance, dornase alfa + hypertonic saline, inhaled tobramycin/aztreonam for chronic Pseudomonas, PERT + ADEK vitamins, insulin for CFRD, and 14-day IV two-drug anti-pseudomonal therapy for exacerbations.

Monitoring pillars: Quarterly CF clinic with spirometry and sputum culture; annual OGTT, PHQ-9/GAD-7, fat-soluble vitamins, NTM culture; LFTs q3 months × 1y then annually on modulator; DEXA; colonoscopy starting at age 40 (every 5 years).

Step 3 high-yield decisions: Continue modulators during pregnancy with shared decision-making, dose-reduce ETI for Child-Pugh B (hold for severe hepatotoxicity), screen for CYP3A4 interactions before any new prescription, refer to a CF Foundation–accredited center, plan structured pediatric-to-adult transition, and refer for lung transplant evaluation when FEV₁ <30% or with rapid decline/recurrent ICU exacerbations.

Board pearl: The single most testable conceptual pivot in adult CF is "variant determines therapy" — CFTR genotyping is not a luxury, it is the gateway to disease-modifying treatment and the linchpin of every Step 3 management vignette in this topic.