Cystic Fibrosis: Diagnosis & Investigations

Diagnostic Criteria (CFF Consensus Guidelines)

• Characteristic phenotypic features (sinopulmonary disease, GI/nutritional abnormalities, salt loss, male urogenital abnormalities)
• Family history of CF in a first-degree relative
• Positive newborn screening (NBS) result

• Sweat chloride ≥60 mmol/L (diagnostic)
• Sweat chloride in the intermediate range (30–59 mmol/L) plus identification of two disease-causing CFTR mutations
• Sweat chloride in the intermediate range plus demonstration of abnormal nasal epithelial ion transport (nasal potential difference or intestinal current measurement)

Diagnostic Algorithm

1. Newborn Screening (NBS)

• The most common NBS test measures immunoreactive trypsinogen (IRT) in blood — elevated because pancreatic injury in CF causes trypsinogen to leak into circulation.
• Over 60% of CF patients in the USA are now diagnosed via NBS (median age at diagnosis: 4 months).
• A positive NBS is presumptive only — must be confirmed with sweat chloride testing ± genetic analysis.
• Sleisenger & Fordtran's GI & Liver Disease

2. Sweat Chloride Testing — The Gold Standard

• Updated CFF guidance lowered the intermediate range threshold from 40 to 30 mmol/L, improving detection of milder/atypical CF without increasing false positives.
• The test should be performed at a certified CF center using standardized methods — false positives and false negatives occur with malnutrition, certain medications, or inadequate sweat volume.
• Conditions other than CF that raise sweat electrolytes include ectodermal dysplasia, adrenal insufficiency, glycogen storage disease type 1, familial hypoparathyroidism, and mucopolysaccharidoses.
• Harrison's Principles of Internal Medicine 22E; Sleisenger & Fordtran's

3. CFTR Genetic Analysis (Second-Line)

• Triggered by an intermediate sweat chloride (30–59 mmol/L) or when confirmation is needed.
• Full CFTR sequencing (or high-sensitivity panel) is preferred — standard panels testing <40 mutations are insufficient for atypical/mild cases, as they are biased toward common Caucasian mutations and will miss rare partial-function variants.
• Two CF-causing mutations = CF confirmed.
• One or zero mutations with intermediate sweat Cl⁻ → proceed to third-line physiologic testing.
• Genotype information is catalogued in the CFTR-2 repository (cftr2.org), useful for predicting phenotypic severity and guiding mutation-specific therapy.
• Murray & Nadel's Textbook of Respiratory Medicine; Thompson & Thompson Genetics 9e

4. CFTR Physiologic Testing (Third-Line)

5. Ancillary Investigations

CFTR-Related Spectrum

• Classic CF (pancreatic-insufficient): most severe; biallelic severe CFTR mutations; sweat Cl⁻ ≥60
• Atypical/nonclassic CF: milder; often one severe + one mild mutation; may have normal/borderline sweat Cl⁻
• CFTR-related metabolic syndrome (CRMS) / CFSPD: positive NBS + intermediate sweat Cl⁻ + <2 CF-causing mutations; not CF but at risk
• CFTR-related disorders (CFTR-RD): isolated manifestations (CBAVD, idiopathic pancreatitis, bronchiectasis) in patients who don't meet full CF criteria but carry CFTR mutations

Important Caveats

• <2% of patients with classic CF phenotype have normal sweat chloride — molecular CFTR analysis is essential in these cases.
• Some patients exhibit CF-like disease without identifiable CFTR mutations — may be due to mutations in the epithelial sodium channel (ENaC) gene or non-coding CFTR regions.
• Rare CFTR mutations not on standard panels are enriched in patients with atypical/adult-onset CF — always use full sequencing in this population.

Tuberculous Meningitis: New Treatment Guidelines

Overview

1. Anti-Tuberculosis Chemotherapy

Standard Drug-Susceptible TBM (Adults)

• Isoniazid: 300 mg/day (5 mg/kg) + pyridoxine 50 mg/day (to prevent peripheral neuropathy)
• Rifampicin: 10 mg/kg/day (max 600 mg)
• Pyrazinamide: weight-based (1000–2000 mg/day)
• Ethambutol: 15–25 mg/kg/day

• WHO recommends 12 months total; there is currently no evidence supporting longer durations producing better outcomes.
• The SURE trial (ISRCTN40829906) comparing a 6-month intensive regimen vs. 12-month standard for childhood TBM is expected to report results by end of 2025/early 2026.
• Relapse is uncommon regardless of regimen; most deaths occur in the first 6 months.
• Harrison's Internal Medicine 22E; 2026 Lancet Infect Dis Guideline

Paediatric TBM — The Cape Town Regimen

• Single phase, 6–9 months, once daily × 7 days/week
• Elevated doses to compensate for poor CNS penetration:
  • Isoniazid: 15–20 mg/kg/day (max 450 mg)
  • Rifampicin: 22.5–30 mg/kg/day (max 900 mg)
  • Pyrazinamide: 35–45 mg/kg/day (max 2 g)
  • Ethionamide: 17.5–22.5 mg/kg/day (max 1 g) — used instead of ethambutol for better CNS penetration
• 2024 SA NDoH Paediatric TB Guideline; 2026 Lancet Guideline

2. High-Dose Rifampin — NOT Recommended (New Evidence)

• 499 adults (61% HIV-positive) in Indonesia, South Africa, Uganda
• High-dose rifampin (35 mg/kg/day) vs standard (10 mg/kg/day) for 8 weeks
• Result: No benefit. 6-month mortality was 44.6% (high-dose) vs 40.7% (standard); HR 1.17 (95% CI 0.89–1.54; P = 0.25)
• Drug-induced liver injury was higher with high-dose rifampin (8.0% vs 4.4%)
• Conclusion: High-dose rifampin cannot be recommended for TBM

⚠️ This negates earlier promising phase II data and should update clinical practice.

3. Adjunctive Corticosteroids — Revised Recommendations

HIV-Negative Patients

• Dose: 0.4 mg/kg/day (or 12–16 mg/day) IV for 3–4 weeks, then taper over 3 weeks
• Reduces mortality and severe disability in HIV-negative adults and adolescents

HIV-Positive Patients — Landmark Change

• 520 HIV-positive adults with TBM (Vietnam, Indonesia); double-blind, placebo-controlled
• Dexamethasone vs placebo for 6–8 weeks
• Result: No survival benefit. Mortality: 44.1% (dexamethasone) vs 49.0% (placebo); HR 0.85 (95% CI 0.66–1.10; P = 0.22)
• No subgroup demonstrated clear benefit; serious adverse events were similar

⚠️ This is a practice-changing finding. Dexamethasone should not be routinely used in HIV-positive patients with TBM. The 2026 Lancet guideline incorporates this finding.

• Evidence-based recommendation: dexamethasone for HIV-negative TBM
• No clear recommendation for universal use in HIV-positive TBM

4. Drug-Resistant TBM

Multidrug-Resistant TBM (MDR-TBM)

• Mortality from MDR-TBM (resistant to rifampicin + isoniazid) exceeds 70%
• Poor outcomes driven by delayed resistance detection and uncertain CNS efficacy of second-line drugs
• No RCTs currently exist to guide MDR-TBM treatment
• The 2026 guideline provides good practice points (expert opinion only):
  • Detect resistance early — use rapid molecular testing (Xpert MTB/RIF)
  • Switch to second-line regimens incorporating fluoroquinolones (levofloxacin, moxifloxacin) — excellent CNS penetration
  • Consider linezolid, bedaquiline, and other Group A/B MDR drugs, though CNS data are limited
  • PET imaging studies with radiolabelled antibiotics are providing emerging insights on CNS drug distribution

Isoniazid-Monoresistant TBM

• High-dose rifampin + levofloxacin showed a survival benefit in a phase III study in isoniazid-resistant TBM (Heemskerk et al., 2016) — fluoroquinolones may replace INH in this scenario
• Goodman & Gilman's Pharmacological Basis of Therapeutics

5. Fluoroquinolones

• Excellent CNS penetration (unlike ethambutol and streptomycin)
• Levofloxacin/moxifloxacin: Added to initial regimens by many experts, especially when drug susceptibility is uncertain or in isoniazid-resistant cases
• Moxifloxacin is a Group A drug for MDR-TB pulmonary disease; its role in TBM is promising but data remain limited
• The AAP Red Book recommends adding a fluoroquinolone to initial empiric regimens for suspected TBM, particularly when susceptibility is unknown

6. Neurocritical & Neurosurgical Care

7. Antiretroviral Therapy in HIV-Co-infected Patients

• Start ART promptly — but timing relative to anti-TB treatment must account for immune reconstitution inflammatory syndrome (IRIS) risk, which can paradoxically worsen TBM
• Expert opinion favours ART initiation after clinical stabilisation (typically 2–8 weeks after TB treatment), though evidence is limited
• The 2026 guideline provides guidance on ART timing as part of its neurocritical care recommendations

Summary: What's New in 2026

Cystic Fibrosis: Diagnosis, Treatment & Management

Pathophysiology — The Basis for Treatment

Part 1 — Diagnosis

Diagnostic Criteria (CFF Consensus Guidelines)

• Characteristic phenotypic features (sinopulmonary disease, GI/nutritional abnormalities, salt-loss syndromes, male urogenital abnormalities)
• Family history of CF in a first-degree relative
• Positive newborn screening (NBS) test

• Sweat chloride ≥60 mmol/L, OR
• Sweat chloride 30–59 mmol/L (intermediate) + two CF-causing CFTR mutations, OR
• Sweat chloride intermediate + abnormal nasal potential difference (NPD) or intestinal current measurement (ICM)

The Diagnostic Algorithm

• Immunoreactive trypsinogen (IRT) in blood — elevated due to pancreatic injury
• Over 60% of US patients now diagnosed this way (median age: 4 months)
• Positive NBS must be confirmed with sweat chloride testing

• Triggered by intermediate sweat chloride
• Full CFTR sequencing preferred over limited panels (which miss rare mutations)
• Two CF-causing mutations = diagnosis confirmed
• Reference: CFTR-2 database for genotype-phenotype correlation

• Nasal potential difference (NPD): available at CF research centres
• Intestinal current measurement (ICM): requires rectal biopsy; very limited availability

Disease Spectrum

Part 2 — CFTR Modulator Therapy (Disease-Modifying)

Mutation Classes and Modulator Types

Approved CFTR Modulators

Elexacaftor/Tezacaftor/Ivacaftor (ETI / Trikafta) — The Standard of Care

• Improves FEV₁ by ~14% predicted; reduces pulmonary exacerbations by ~63%; dramatically improves quality of life, weight, and sweat chloride
• Now approved down to age 2 years
• Approved for any CFTR mutation producing a CFTR protein (expanded FDA approval, 2025)
• Monitoring required: liver function tests (hepatotoxicity, though rare); mental health (anxiety, depression, "mental fog" reported in a minority)
• Murray & Nadel's Textbook of Respiratory Medicine; Thompson & Thompson Genetics 9e

Vanzacaftor/Tezacaftor/Deutivacaftor (VTD / Alyftrek) — New in 2024

• 12 years+ with multiple genotypes (F508del-MF and other ETI-eligible)
• VTD non-inferior to ETI on FEV₁ at 24 weeks, with superior sweat chloride reduction (greater CFTR functional restoration)
• Once-daily dosing (vs ETI's twice-daily ivacaftor component)
• Approved Dec 2024 for ages 6+; also covers 31 additional rare mutations not previously eligible for modulators

Post-ETI Supportive Therapy Reduction

• Patients on ETI who discontinued both hypertonic saline and dornase alfa showed no meaningful change in FEV₁ or lung clearance index
• Significant reduction in treatment burden reported
• Key practice implication: many supportive inhaled therapies can be de-escalated in patients on highly effective modulators (HEMTs) — but should be done in shared decision-making

Mutations Without Modulator Options (Class I)

• ~10% of patients have class I (nonsense) mutations producing no CFTR protein — current modulators are ineffective
• Gene therapy, mRNA replacement, and CRISPR-Cas9 approaches are under active investigation but not yet approved

Part 3 — Pulmonary Management

Physical Airway Clearance (Daily — Standard of Care)

• Chest physiotherapy (manual vibropercussion, oscillating vest systems)
• Positive expiratory pressure (PEP) devices, flutter valves, active cycle of breathing
• Aerobic exercise (70–85% max HR) — improves mucus clearance and exercise tolerance
• Pulmonary rehabilitation for severe disease

Mucoactive / Airway Rehydration Therapies

Anti-Infective Therapy

• Early detection and aggressive eradication is critical — chronic colonisation markedly accelerates pulmonary decline
• Inhaled tobramycin (TOBI) or aztreonam (Cayston) alternating monthly; or inhaled ciprofloxacin (dry powder)
• IV antibiotics (tobramycin + anti-pseudomonal β-lactam) for pulmonary exacerbations

• Chronic suppressive inhaled antibiotics (tobramycin, aztreonam, colistin)
• IV course (2–3 weeks) for acute exacerbations, typically at a CF centre

Anti-Inflammatory Therapy

• Azithromycin (250–500 mg, 3× weekly): reduces pulmonary exacerbations by ~40% through anti-inflammatory and anti-biofilm mechanisms; standard of care for patients with Pseudomonas colonisation
• Ibuprofen (high-dose): slows FEV₁ decline in children aged 5–13; under-utilised due to monitoring requirements
• Systemic corticosteroids: for ABPA; not routinely used for CF lung disease

Pulmonary Exacerbations

• Defined by worsening respiratory symptoms, ↓FEV₁, increased sputum
• Treated with IV antibiotics (typically 14–21 days), intensified airway clearance, nutritional support
• Goal: return FEV₁ to baseline — failure to recover predicts long-term decline
• Hospital or home IV therapy depending on severity

Lung Transplantation

• Indicated when FEV₁ <30% predicted, rapid decline, or refractory respiratory failure
• Bilateral sequential lung transplant is standard; median post-transplant survival ~6 years
• Listing criteria: 2-year survival on transplant >50%
• ETI can delay need for transplant significantly; not a contraindication to transplant

Part 4 — Gastrointestinal & Nutritional Management

Pancreatic Exocrine Insufficiency (85–90% of patients)

• Pancreatic enzyme replacement therapy (PERT): lipase 500–2500 units/kg/meal; dose titrated to stool consistency and weight gain
• Standard: enteric-coated microsphere preparations (Creon, Zenpep)
• Always taken with meals and snacks; do not crush

Nutritional Support

• CF is a hypermetabolic state; caloric needs are 120–150% of normal
• Target BMI ≥50th percentile (children), ≥22 kg/m² (adult women), ≥23 kg/m² (adult men)
• Fat-soluble vitamins (A, D, E, K) must be supplemented — malabsorption is universal in PI
• High-calorie diet with supplemental enteral feeds via gastrostomy if needed
• ETI markedly improves nutritional status and weight in most patients
• ESPEN-ESPGHAN-ECFS Nutrition Guideline 2024 (PMID 38169175)

Specific GI Complications

Part 5 — Monitoring & Multidisciplinary Management

Routine Monitoring Schedule

Multidisciplinary CF Team

• Pulmonologist, gastroenterologist, dietitian, physiotherapist, CF specialist nurse, pharmacist, social worker, psychologist
• Segregation protocols: patients should not share waiting rooms or equipment — organisms can spread between patients (especially P. aeruginosa and B. cepacia)

Reproductive Considerations

• ~95% of males are infertile (CBAVD/obstructive azoospermia) — sperm retrieval for ICSI possible
• Women have reduced fertility but can conceive; pregnancy management requires specialist input
• Preconception genetic counselling; carrier screening for partners

Summary: What Has Changed (2024–2025)