---

Interstitial Lung Disease (ILD)

• Harrison's Principles of Internal Medicine 22E, Chapter 304

---

Classification

---

Pathogenesis

• Epithelial injury - recurrent microinjury to alveolar epithelial type II cells triggers aberrant repair
• Fibroblast/myofibroblast activation - driven by TGF-β, connective tissue growth factor (CTGF), endothelin-1
• Immune dysregulation - CD45Ro+ memory T cells, Th1/Th2 cytokine imbalance, germinal centers in CTD-ILD
• Pro-inflammatory cytokines - IL-8, TNF-α, MIP-1α, RANTES accumulate in BAL fluid
• Genetic susceptibility - MHC class II associations (especially in SSc), MUC5B promoter variant (linked to UIP/IPF phenotype in RA-ILD)

---

Clinical Features

• Progressive exertional dyspnea (most common)
• Dry, nonproductive cough
• Fatigue, weight loss in advanced disease
• Extrapulmonary features when associated with CTD (skin changes, joint swelling, Raynaud's phenomenon)

• Bibasilar "Velcro" crackles (fine inspiratory rales) - hallmark finding
• Digital clubbing (especially in IPF)
• Signs of pulmonary hypertension in advanced disease (RV heave, loud P2)
• Cyanosis in end-stage disease

• Restrictive pattern: reduced TLC, FVC, FEV1/FVC ratio preserved or elevated
• Reduced DLCO - often the most sensitive early marker
• Reduced 6-minute walk distance (6MWD)

---

Diagnosis

Step 1 - History and Exposure Assessment

Step 2 - HRCT Chest

Step 3 - Diagnostic Algorithm for IPF

1. Exclusion of other known causes (CTD, drugs, occupational exposures)
2. AND either:
   • HRCT showing a UIP pattern, OR
   • Specific HRCT + histopathology UIP combination (surgical lung biopsy showing subpleural honeycombing + fibroblast foci with temporal/spatial heterogeneity)

Step 4 - Serologies and BAL

• ANA, anti-dsDNA, RF, anti-CCP, anti-Scl-70, anti-Jo-1, anti-synthetase antibodies
• BAL cellular differential (lymphocytosis suggests HP or NSIP; eosinophilia suggests eosinophilic pneumonia)
• Transbronchial cryobiopsy - yields diagnostic histopathology in ~80% of cases; has largely supplanted VATS biopsy in many centers

---

Major ILD Entities

Idiopathic Pulmonary Fibrosis (IPF)

• Most common ILD of unknown cause; prevalence 50-200/100,000
• Typically men in the 5th-6th decade; strong association with smoking
• UIP is the histopathologic pattern: fibroblast foci, honeycombing, temporal/spatial heterogeneity
• Poor prognosis: estimated 50% 3-5 year survival
• Complicated by pulmonary hypertension (PH) in 30-50%, which dramatically worsens prognosis (median survival <1 year when PASP >50 mmHg)

NSIP

• Bilateral symmetric ground-glass opacities; subpleural sparing
• Commonly associated with CTD (especially SSc, DM/PM)
• Responds better to immunosuppression than IPF; better prognosis
• Histology: uniform interstitial fibrosis without fibroblast foci; temporally homogeneous

Cryptogenic Organizing Pneumonia (COP)

• Subacute onset; bilateral subpleural consolidation; reversed halo sign
• Responds dramatically to corticosteroids (>80% response)
• Can relapse on steroid taper

Hypersensitivity Pneumonitis (HP)

• Caused by inhaled antigens (bird proteins, molds, chemicals)
• Acute, subacute, and chronic forms
• Chronic HP can be fibrotic and difficult to distinguish from IPF

CTD-ILD

• SSc-ILD: Most common CTD-ILD; NSIP pattern predominates; treat with mycophenolate or cyclophosphamide
• RA-ILD: Male predominance (3:1); both UIP and NSIP patterns; UIP carries worse prognosis
• DM/PM-ILD: Up to 45% with anti-synthetase antibodies develop ILD; anti-Jo-1 most common; NSIP ± COP pattern

---

Treatment

General Measures (all ILDs)

• Smoking cessation - essential
• Supplemental oxygen when indicated (improves exercise tolerance, reduces PH risk)
• Pulmonary rehabilitation - improves exercise capacity and quality of life
• Treat comorbidities - GERD (microaspiration is a trigger), PH, sleep apnea
• Vaccinations - influenza, pneumococcal

Antifibrotic Therapy (IPF)

Emerging Treatments (2025-2026 data)

• Preferential PDE4B inhibitor with antifibrotic and immunomodulatory effects
• 1,177 patients (77.7% already on nintedanib or pirfenidone)
• Nerandomilast 18 mg BID vs placebo: FVC decline -114.7 ml vs -183.5 ml (difference +68.8 ml, p<0.001)
• Effective on top of standard antifibrotic therapy
• Main adverse effect: diarrhea (41.3% with 18 mg dose)

• A prostacyclin analog previously used for pulmonary hypertension; has antifibrotic preclinical data
• 593 patients; 75.4% on background antifibrotic therapy
• Treprostinil vs placebo: FVC change -49.9 ml vs -136.4 ml (difference +95.6 ml, p<0.001)
• Also reduced clinical worsening (HR 0.71; p=0.02)
• Main adverse effect: cough (48.3% vs 24.1%)

Immunosuppression

• Not indicated in IPF - the PANTHER trial showed immunosuppression (prednisone + azathioprine + NAC) increased mortality in IPF
• Used in CTD-ILD (SSc, RA, DM/PM):
  • Mycophenolate mofetil (first-line for SSc-ILD; SLS II trial)
  • Cyclophosphamide (SLS I trial; induction for severe/rapidly progressive CTD-ILD)
  • Rituximab for refractory DM/PM-ILD
  • Corticosteroids for COP, HP (acute), sarcoidosis

Lung Transplantation

• Remains the only option that can extend survival in advanced IPF
• Bilateral lung transplant preferred over single-lung transplant
• Pre-transplant PH significantly increases risk of primary graft dysfunction
• Combined emphysema + pulmonary fibrosis: PH prevalence 30-50%, 1-year survival as low as 48% if PVR elevated

---

Monitoring and Prognosis

• Serial PFTs every 3-6 months: >10% decline in FVC or >15% decline in DLCO indicates disease progression
• 6-minute walk test: distance and oxygen desaturation are prognostic markers
• HRCT: progression of fibrosis (honeycombing, traction bronchiectasis)
• GAP index (Gender, Age, Physiology): validated prognostic model for IPF based on FVC and DLCO

Poor prognostic factors in IPF:

• Extensive fibrosis on HRCT
• Low DLCO (<40% predicted)
• PH at rest (mPAP >25 mmHg)
• Rapid FVC decline (>10%/year)
• Acute exacerbations (5-10% annual incidence; 50-90% in-hospital mortality)

---

Summary Table

---

---

Bronchodilators

1. β₂ Adrenergic agonists (sympathomimetics)
2. Anticholinergic agents (muscarinic receptor antagonists)
3. Methylxanthines (theophylline)

• Goodman & Gilman's Pharmacological Basis of Therapeutics, Ch. 44

---

1. β₂ Adrenergic Agonists

Chemistry

Mechanism of Action

• Opening of Ca²⁺-activated K⁺ channels → membrane hyperpolarization
• Decreased phosphoinositide hydrolysis
• Decreased myosin light chain kinase (MLCK) activity + increased MLC phosphatase activity
• Net result: smooth muscle relaxation regardless of the bronchoconstrictor stimulus (functional antagonism)

• Inhibition of mast cell mediator release
• Reduction of microvascular leakage (reduces mucosal edema)
• Enhanced mucociliary clearance (increased ion transport, mucus secretion)
• Presynaptic β₂ receptor activation → inhibits ACh release from cholinergic nerves

Key point: β₂ agonists do NOT suppress chronic airway inflammation - regular use does not reduce eosinophils or activated inflammatory cells in the airways.

Classification by Duration

• Salmeterol - long aliphatic side chain anchors to an "exosite" within the receptor binding cleft
• Formoterol - bulky substitution + moderate lipophilicity keeps the drug in the membrane near the receptor (slow-release effect); also has rapid onset and can serve as reliever
• Ultra-LABAs (indacaterol, vilanterol, olodaterol) - exceed 24 h duration; once-daily dosing

Clinical Use

• SABAs (albuterol) are the first-line rescue therapy for acute symptoms
• If symptoms require rescue >2×/week, FEV₁ <80% predicted, or nocturnal symptoms >2×/month → add low-dose ICS
• LABAs are never used as monotherapy in asthma (risk of fatal attacks without ICS coverage); always combined with ICS
• GINA guidelines recommend budesonide/formoterol combination as both maintenance AND reliever (SMART/AIR strategy)

• SABAs and long-acting agents both used; inhaled bronchodilators are the foundation of COPD treatment
• Regular maintenance with LABA and/or LAMA reduces dyspnea and exacerbation frequency

Adverse Effects (β₂ Agonists)

---

2. Anticholinergic Agents (Muscarinic Antagonists)

Mechanism of Action

• Bronchoconstriction from vagal tone
• Mucus secretion from submucosal glands

Note: M2 receptors on presynaptic cholinergic nerves normally inhibit ACh release (auto-inhibition). Blockade of M2 receptors (as occurs with ipratropium) can paradoxically increase ACh release - this is why ipratropium occasionally causes paradoxical bronchoconstriction.

Classification by Duration

Clinical Use

• LAMAs are first-line maintenance agents; they improve functional capacity and significantly reduce exacerbation frequency
• Tiotropium is the most studied LAMA; shown to reduce exacerbations, hospitalizations, and improve quality of life
• Mixed data on whether LAMAs slow the rate of FEV₁ decline in COPD

• Ipratropium has modest bronchodilator effect (similar magnitude to β₂ agonists at baseline) but used mainly as an alternative when β₂ agonists are not tolerated
• In acute severe asthma, combination ipratropium + SABA reduces hospitalization rates
• Tiotropium (LAMA) added to ICS in severe asthma is comparable in effect to adding a LABA; adding tiotropium to ICS/LABA triple therapy further reduces exacerbations in patients with persistent obstruction, high symptom burden, and exacerbation history

Adverse Effects (Anticholinergics)

---

3. Methylxanthines (Theophylline)

Mechanism of Action

• Non-selective PDE inhibition → ↑ cAMP and cGMP → smooth muscle relaxation
• Adenosine receptor antagonism (A1, A2A) → bronchodilation and reduced bronchoconstriction
• Histone deacetylase (HDAC) activation (at low therapeutic doses) → anti-inflammatory effects; restores steroid sensitivity in COPD and severe asthma
• Stimulation of respiratory center (increases hypoxic/hypercapnic ventilatory drive)

Pharmacokinetics

• Metabolized by CYP1A2 and CYP3A4 in the liver
• Narrow therapeutic window: therapeutic range 5-15 mg/L (or 55-85 μmol/L); toxicity begins at >20 mg/L
• Half-life ~8 h (highly variable): shortened by smoking, enzyme inducers; prolonged by heart failure, liver disease, older age, enzyme inhibitors (e.g., erythromycin, ciprofloxacin, cimetidine)

Clinical Use

• COPD: low-dose theophylline used as add-on when response to inhaled bronchodilators is insufficient; reduces dyspnea, improves mucociliary clearance
• Asthma: third-line agent due to toxicity concerns; sustained-release preparations used as maintenance
• Neonatal apnea: IV aminophylline (theophylline ethylenediamine) or caffeine

Adverse Effects

---

4. PDE4 Inhibitors (Selective)

• Inhibits PDE4 → ↑ cAMP in inflammatory cells (mast cells, eosinophils, neutrophils, T cells, macrophages)
• Anti-inflammatory effect rather than direct bronchodilation
• Used as add-on therapy when patients have repeated exacerbations despite triple inhaler therapy (ICS/LABA/LAMA)
• Side effects: nausea, diarrhea, weight loss, headache, psychiatric effects (depression, suicidal ideation - black box warning)

---

Inhaled Bronchodilator Drug Reference Table

• Fishman's Pulmonary Diseases and Disorders, Table 40-7

Fixed-Dose Combination Inhalers (COPD)

Triple inhalers are more effective than LABA/LAMA or ICS/LABA combinations at reducing exacerbations in COPD and may also reduce cardiovascular mortality.

---

Step-Up Approach in COPD

---

Comparison: β₂ Agonists vs Anticholinergics

---

Novel Classes in Development

• MABA (Muscarinic Antagonist - Beta Agonist dual action): Single molecule with both LAMA and LABA activities; balancing the two activities has been challenging in development
• Selective PDE inhibitors: PDE4B-selective agents (e.g., nerandomilast - approved for IPF, also under study for airway disease)
• Rho-kinase inhibitors: Target airway smooth muscle contraction at a post-receptor level

---

---

Tuberculous Meningitis (TBM)

• Adams and Victor's Principles of Neurology, 12th Ed., Ch. 31

---

Epidemiology & Risk Factors

• Incidence parallels systemic TB prevalence; markedly higher in sub-Saharan Africa, South/Southeast Asia
• HIV co-infection is the dominant risk factor: TB incidence is ~500x higher in AIDS patients; TBM may be the first clinical manifestation of HIV
• Other risk factors: alcoholism, malnutrition, extremes of age, immigrants from high-prevalence regions (Asia, Africa, India, former Soviet states)
• Drug-resistant TBM is an increasing concern, particularly with MDR-TB strains

---

Pathogenesis

1. Bacteremia and seeding: M. tuberculosis reaches the CNS via hematogenous spread (typically from a primary pulmonary focus). Bacilli seed the meninges and subpial brain regions, forming small tubercles (Rich foci) in the meningeal or subependymal layers
2. Rupture and subarachnoid spread: One or more tubercles ruptures, discharging bacteria directly into the subarachnoid space, triggering the full meningitic syndrome

TBM may also complicate miliary tuberculosis (hematogenous dissemination), where TB seeds the whole body including the meninges simultaneously.

---

Pathology

• Thick gelatinous basal exudate obliterates the pontine, interpeduncular, and perimesencephalic cisterns; extends around the medulla, optic chiasm, floor of third ventricle, and undersurfaces of the temporal lobes
• Microscopy: Central caseation → surrounded by epithelioid cells, Langhans giant cells, lymphocytes, plasma cells → fibrin exudate in CSF
• Cranial nerves traversing the basal cisterns are involved more often than in bacterial meningitis (20% of cases at presentation)
• Arteritis: Perforating arteries supplying the basal ganglia, internal capsule, and brainstem undergo inflammatory endarteritis → ischemic infarction (stroke)
• Hydrocephalus: Basal cistern obliteration → communicating hydrocephalus (most common); ependymitis blocking the aqueduct → obstructive hydrocephalus (less common)
• Spinal involvement: Meningeal exudate extends around the cord → myeloradiculitis, posterior/lateral column signs

MRI in TBM - Gadolinium Enhancement of Basal Meninges

---

Clinical Features

Onset

• Subacute - hallmark feature. Symptoms evolve over 1-2 weeks (occasionally longer), in sharp contrast to the hours-to-days of bacterial meningitis

Prodromal symptoms (days to weeks before meningism)

• Low-grade fever
• Malaise, fatigue
• Personality change, irritability
• Headache (>50% of cases)

Meningitic stage

• Persistent headache and fever (most consistent findings)
• Neck stiffness (75% of cases); Kernig and Brudzinski signs
• Confusion, lethargy, altered consciousness
• Nausea, vomiting

Later/advanced features

• Cranial nerve palsies (20% at presentation): CN III, IV, VI (ocular palsies) most common; less often CN VII (facial), CN VIII (deafness)
• Papilledema (raised ICP due to hydrocephalus)
• Focal neurologic deficits from cerebral infarction (basal ganglia, internal capsule)
• Seizures (20-25%)
• Hypothermia and hyponatremia (SIADH is common)
• Stupor and coma in advanced disease

In infants and young children: apathy, hyperirritability, vomiting, and seizures predominate; neck stiffness may be absent, making early diagnosis especially difficult.

---

British MRC Staging

---

Diagnosis

Lumbar Puncture - CSF Analysis

A CSF glucose:serum protein ratio <0.5 is a key diagnostic clue. CT of the head may be normal in 30% of mild cases, so a normal CT does not exclude TBM.

Key Diagnostic Tests

MRI/CT Brain

• MRI (with gadolinium) is the preferred neuroimaging modality
• Classic findings: basilar meningeal enhancement, hydrocephalus, infarcts (especially basal ganglia), tuberculomas
• Tuberculoma on MRI: thick ring-enhancing lesion that may mimic brain tumor (see Fig. 31-4)

---

Treatment

Antituberculous Drugs

Intensive Phase (first 2 months): Four-drug regimen

INH and PZA have the best CNS penetration among first-line drugs. Rifampicin penetration is limited with normal meninges but improves significantly with inflammation.

Continuation Phase (months 3-9/12)

• Continue INH + RMP for 7-10 more months (total 9-12 months)
• Some guidelines extend to 12 months for TBM (vs 6 months for pulmonary TB)
• Pyridoxine (vitamin B6) 50 mg/day given with INH to prevent peripheral neuropathy (especially in alcoholics, diabetics, pregnant women, HIV patients)

Alternative Regimen (drug-resistant/severe cases)

• INH + PZA + high-dose RMP + moxifloxacin (fluoroquinolone with excellent CNS penetration)
• In MDR-TBM: add ethionamide (15-25 mg/kg/day in divided doses after meals; risk of optic neuropathy and gastric irritation)
• Duration extended to 18-24 months for MDR-TBM

Corticosteroids (Adjunctive Therapy) - MANDATORY

• Dose: 0.4 mg/kg/day IV for 2-4 weeks, then tapered over 4-8 weeks (total 6-8 weeks)
• Benefit: Reduces mortality and severe disability, particularly in MRC Grade II-III
• Reduces meningeal inflammation and vasculitis → less ischemic injury
• Particularly beneficial in non-HIV patients; benefit in HIV co-infection is less clear but still recommended

Based on the landmark Thwaites et al. NEJM 2004 trial, dexamethasone reduced 9-month mortality from 41% to 31% in HIV-negative TBM patients. It is now standard of care globally.

Neurosurgical Interventions

• Hydrocephalus requiring intervention: up to 25% of patients
  • External ventricular drainage (acute, severe hydrocephalus)
  • Ventriculoperitoneal (VP) shunt (communicating hydrocephalus refractory to medical management)
  • Endoscopic third ventriculostomy (obstructive hydrocephalus at aqueduct level)
• Repeat lumbar punctures can temporarily reduce ICP

---

2025 Update - High-Dose Rifampicin Trial

• 499 adults with TBM in Indonesia, South Africa, Uganda; 60.9% HIV co-infected
• High-dose rifampicin (cumulative 35 mg/kg/day) vs standard dose (10 mg/kg/day) for 8 weeks, on background standard 4-drug therapy
• Primary outcome (6-month mortality): 44.6% vs 40.7% - no significant difference (HR 1.17; p = 0.25)
• High-dose group had earlier deaths (median time to death 13 vs 24 days) and more drug-induced liver injury (8.0% vs 4.4%)
• Conclusion: High-dose oral rifampicin did not improve survival and may be harmful - standard dosing remains the recommendation

---

Complications

---

Prognosis

• Overall mortality: 20-50% (higher in HIV-positive, Grade III, drug-resistant)
• Long-term neurologic sequelae in survivors: ~50%
  • Cognitive impairment, memory deficits
  • Focal motor deficits from infarction
  • Epilepsy
  • Cranial nerve deficits (visual loss, hearing loss)
  • Hydrocephalus requiring shunting
  • Hypothalamic/pituitary dysfunction
• Prognostic factors (poor outcome):
  • MRC Grade III at presentation
  • HIV co-infection
  • Drug-resistant organisms
  • Extreme age (infants, elderly)
  • Delay in diagnosis and treatment initiation
  • Cerebral infarction on imaging

---

HIV and TBM

• TBM in HIV patients may progress faster with more frequent multi-organ involvement
• ART should be deferred 2-8 weeks after starting anti-TB treatment to reduce risk of TB-IRIS (severe paradoxical worsening from immune reconstitution)
• CD4 count <50 cells/μL: start ART within 2 weeks; CD4 50-200: can defer up to 8 weeks
• HIV treatment does not fundamentally change TBM management but TB-IRIS can be severe and life-threatening

---

Summary