RespiratoryTier 2Disease (DEADMAN)

Cystic fibrosis

Description

Autosomal recessive multisystem exocrinopathy from CFTR dysfunction (chr 7q31)
- CFTR = cAMP-regulated chloride/bicarbonate channel on apical epithelium
- Loss -> dehydrated, acidic, viscid secretions -> obstruction, infection, fibrosis of every ducted organ

Classic vs non-classic

	Classic	Non-classic
Sweat Cl	>60 mmol/L	Intermediate (30-59) or normal
Pancreas	Insufficient (~85%)	Sufficient; pancreatitis 5-20%
Lung	Obstructive from infancy	Variable, later onset
Other	Meconium ileus 15-20%, liver disease 5-10%, CBAVD	CBAVD, sinusitis

CFTR-related disorders - single-organ phenotypes without full CF: isolated CBAVD, recurrent pancreatitis, disseminated bronchiectasis

Mutation classes - determine which modulator works

Class	Defect	Example	Modulator
I	No protein (nonsense/frameshift)	G542X, W1282X	None - no protein to modulate
II	Misfolded, degraded	F508del (~70% of alleles)	Corrector + potentiator
III	Gating	G551D	Potentiator (ivacaftor)
IV	Reduced conductance	R117H	Potentiator
V	Reduced quantity	3849+10kbC>T	Potentiator +/- corrector
VI	Reduced stability	4326delTC	Stabiliser

I-III = "minimal function", severe, pancreatic insufficient. IV-VI = residual function, milder, often pancreatic sufficient

Epidemiology

Commonest lethal autosomal recessive disease in Caucasians
~1:2500 live births; carrier frequency ~1:25
~3800 people with CF in Australia; median predicted survival now >50 yr and rising with modulators
Adults now outnumber children - it is a general medicine problem, not a paediatric one
F508del on ~70% of Australian alleles; ~50% homozygous
Rare in African and East Asian populations

Aetiopathogenesis

Airway

dec CFTR Cl- secretion + inc ENaC Na+ absorption
- -> dec airway surface liquid depth -> collapsed periciliary layer
- -> failed mucociliary clearance -> mucus plugging
dec HCO3- secretion -> acidic airway surface liquid
- -> impaired antimicrobial peptide function (defensins, LL-37)
Chronic infection -> massive neutrophilic influx
- Neutrophil elastase overwhelms antiproteases -> airway wall destruction
- NETs + neutrophil-derived DNA -> inc sputum viscosity, biofilm persistence (the dornase alfa target)
-> bronchiectasis, mucus plugging, bronchiolitis, eventual respiratory failure
Vicious cycle: obstruction -> infection -> inflammation -> more obstruction

Pathogen sequence with age

S. aureus and H. influenzae -> P. aeruginosa (mucoid conversion = chronic infection established) -> Burkholderia cepacia complex, Stenotrophomonas, Achromobacter, NTM (M. abscessus), Aspergillus (ABPA)

Other organs

Pancreas - ductal obstruction -> autodigestion -> exocrine insufficiency, later islet destruction -> CFRD
Liver - focal biliary cirrhosis -> multilobular cirrhosis + portal hypertension in 5-10%
Intestine - viscid contents -> meconium ileus (neonate), DIOS (later)
Vas deferens - atresia in utero -> CBAVD in >95% of males (spermatogenesis is normal)
Sweat gland - CFTR normally reabsorbs Cl- from duct; loss -> salty sweat (the diagnostic test)
- -> hyponatraemic hypochloraemic dehydration with metabolic alkalosis in heat

Diagnosis

Diagnostic requirement

One clinical/screening criterion + laboratory evidence of CFTR dysfunction.

Clinical/screening: typical phenotype (meconium ileus, failure to thrive with steatorrhoea, recurrent sinopulmonary infection, nasal polyps, rectal prolapse, male infertility, salt-loss syndrome) OR affected sibling OR positive newborn screen
PLUS one of:
- Sweat chloride >=60 mmol/L on two occasions (pilocarpine iontophoresis)
- Two disease-causing CFTR mutations in trans
- Abnormal nasal transepithelial potential difference / intestinal current measurement

Sweat chloride interpretation


<30	CF unlikely (any age)
30-59	Intermediate - genotype and further testing
>=60	Diagnostic

False positives: malnutrition, adrenal insufficiency, hypothyroidism, eczema, anorexia nervosa, G6PD deficiency
False negatives: oedema, hypoproteinaemia, inadequate sweat volume, some class IV-VI mutations

Newborn screening (Australia, all states)

IRT -> DNA panel -> sweat test
A negative newborn screen does NOT exclude CF if the phenotype fits - the panel misses rare mutations
CRMS/CFSPID - screen-positive, inconclusive diagnosis; requires longitudinal follow-up

Diagnosing in an adult

Suspect in: disseminated bronchiectasis (esp. upper lobe), male infertility with CBAVD, idiopathic recurrent pancreatitis, ABPA, unexplained nasal polyps in adults, chronic P. aeruginosa

Monitoring

Spirometry (FEV1 %pred = the key prognostic variable), sputum culture (incl. NTM, fungal) at least quarterly
Annual: OGTT from age 10 (CFRD), DEXA, fat-soluble vitamins (A, D, E, K), LFTs, liver USS
Faecal elastase for pancreatic status
CT chest for bronchiectasis extent; Lung Clearance Index is more sensitive than FEV1 in early disease

Management

*Multidisciplinary CF centre care, with strict infection segregation (never cohort patients - cross-infection with B. cepacia and M. abscessus).*

1. CFTR modulators - the transformative therapy

Genotype determines eligibility. These treat the basic defect, not the consequences.

Agent	Mechanism	Indication
Ivacaftor	Potentiator - opens the channel	Gating (G551D) and residual-function mutations
Lumacaftor / tezacaftor + ivacaftor	Corrector + potentiator	F508del homozygous (superseded)
Elexacaftor/tezacaftor/ivacaftor (Trikafta)	Dual corrector + potentiator	>=1 F508del; PBS-listed from age 2
Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek)	Next-generation triple, once daily	Broadened to responsive/protein-producing variants

Effect: inc FEV1 ~10-14 points, sweat Cl falls ~40-50 mmol/L, exacerbations dec ~60%, weight gain, improved fertility
No benefit in class I (nonsense/frameshift) - no protein is made. Read-through agents and gene therapy remain investigational
Monitor LFTs; cataract screening in children; drug interactions - strong CYP3A4 inducers (rifampicin, carbamazepine) abolish efficacy
*Pregnancy rates have risen sharply since modulators - contraception and pre-conception counselling are now core CF care*

2. Airway clearance and mucoactive therapy

Physiotherapy daily - PEP, ACBT, oscillatory devices, exercise
Dornase alfa (rhDNase) - cleaves neutrophil DNA -> dec viscosity; inc FEV1, dec exacerbations
Hypertonic saline 6-7% (pre-treat with bronchodilator) or inhaled mannitol
Order matters: bronchodilator -> mucoactive -> clearance -> inhaled antibiotic

3. Infection

*First isolation of P. aeruginosa -> eradication attempt*
- Oral ciprofloxacin + inhaled colistin, or inhaled tobramycin 28 days
- Succeeds in ~70-80% - the single most important window; once mucoid and chronic it is irreversible
*Chronic P. aeruginosa* -> maintenance nebulised tobramycin alternate months** (or colistin, aztreonam)
Azithromycin 3x/week - anti-inflammatory/anti-biofilm; exclude NTM first
Exacerbation: 2 IV antipseudomonal agents from different classes for 10-14 days
- Aminoglycoside clearance is increased in CF - higher mg/kg doses, level-guided
*NTM (M. abscessus) must be excluded before starting azithromycin monotherapy or lung transplant workup*
ABPA - total IgE >1000, Aspergillus-specific IgE; treat with corticosteroid +/- itraconazole

4. Nutrition and GI

PERT with every meal and snack, titrated to stool character; acid suppression improves efficacy
High-energy, high-fat diet (the historical 120-150% of normal energy needs is being revised downward in the modulator era - obesity is now emerging)
Fat-soluble vitamins A, D, E, K; salt supplementation in hot weather
DIOS - Gastrografin or oral polyethylene glycol; distinguish from constipation and appendicitis
CF liver disease - ursodeoxycholic acid (evidence weak); variceal screening; transplant if decompensated

5. CF-related diabetes

~20% of adolescents, ~40-50% of adults - screen with annual OGTT from age 10
Insulin deficiency dominates -> insulin is the only recommended therapy (not oral agents)
Do NOT restrict energy intake; weight loss and FEV1 decline often precede diagnosis by 2-4 years
Micro- and macrovascular complications occur; aminoglycoside exposure compounds renal risk

6. Bone, sinus, reproductive

CF bone disease - vitamin D, calcium, exercise, treat hypogonadism; bisphosphonate if osteoporotic
Nasal polyps and chronic sinusitis - topical steroid, saline, surgery; dupilumab in selected
CBAVD -> obstructive azoospermia; sperm retrieval + ICSI. Female fertility near-normal
Genetic counselling: all children of an affected parent are obligate carriers; screen the partner - if the partner is a non-carrier, risk falls to near-zero

7. Lung transplantation

Bilateral (never single) - the native lung would seed the graft
Refer when: FEV1 <30% and falling, rapid decline, hypercapnia, pulmonary hypertension, frequent ICU/exacerbations, massive haemoptysis
Absolute contraindications: another failing major organ, active malignancy, uncontrolled systemic infection, HIV (historically), active substance use within ~6 months
Relative: B. cepacia complex (esp. B. cenocepacia) - markedly worse survival; M. abscessus; severe malnutrition, non-adherence, symptomatic osteoporosis
Transplant does not treat CF outside the lung - sinusitis, CFRD, DIOS, liver disease and osteoporosis persist or worsen; malabsorption makes calcineurin inhibitor dosing erratic, and steroids worsen CFRD and bone disease

8. Complications - acute

Massive haemoptysis - bronchial artery embolisation; hold NSAIDs and physiotherapy
Pneumothorax - chest drain; pleurodesis complicates future transplant but is not a contraindication

Associations

Bronchiectasis with chronic P. aeruginosa, S. aureus, B. cepacia, NTM
Chronic rhinosinusitis and nasal polyps
ABPA
Exocrine pancreatic insufficiency -> steatorrhoea, fat-soluble vitamin deficiency
CF-related diabetes (~40-50% of adults)
CF liver disease - focal biliary cirrhosis, portal hypertension, gallstones
DIOS, constipation, rectal prolapse, intussusception
Male infertility (CBAVD, >95%)
CF bone disease - osteopenia/osteoporosis, kyphosis, rib fracture
Salt-loss syndrome - hypochloraemic hypokalaemic metabolic alkalosis (may be the presentation in a hot climate)
CF arthropathy, vasculitis, amyloidosis
inc GI malignancy risk (colorectal, small bowel) - colonoscopy screening from age 40, or 30 post-transplant
Depression and anxiety - high prevalence, screened annually

Natural history & complications

Respiratory failure causes >80% of deaths
FEV1 %pred is the dominant prognostic variable; rate of decline matters more than a single value
*Chronic mucoid P. aeruginosa*** -> faster FEV1 decline, more exacerbations, higher mortality
**B. cepacia complex** - risk of "cepacia syndrome" (fulminant necrotising pneumonia with bacteraemia); worse transplant outcomes
Each pulmonary exacerbation leaves a proportion of patients failing to regain baseline FEV1

The modulator era has changed the disease

Median predicted survival has risen from ~30 yr to >50 yr and still climbing
Transplant referrals and paediatric mortality have fallen sharply
New problems: obesity, pregnancy, ageing comorbidity, GI malignancy, mental health, drug interactions
An adult physician will increasingly meet CF as chronic multisystem disease, not as terminal lung disease

Pregnancy

Does not shorten long-term survival, even with moderately reduced FEV1
inc short-term morbidity - requires MDT care, CFRD screening, nutrition
Risk rises with FEV1 <50%, pulmonary hypertension or CFRD

Poor prognostic markers

FEV1 <30%, rapid decline, hypercapnia, pulmonary hypertension
Frequent exacerbations, malnutrition (low BMI), CFRD, massive haemoptysis
B. cepacia or M. abscessus infection, female sex (historically), low socioeconomic status

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