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Approach to Pneumonia

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1. Definition

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2. Classification by Setting

Note: The "HCAP" category has been removed from current IDSA-ATS guidelines due to poor specificity, which drove antibiotic overtreatment. - Fishman's, p. 2255

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3. Epidemiology & Risk Factors

• CAP accounts for 1.5 million annual ED visits in the United States and is the 8th leading cause of death
• Hospitalization rates rise exponentially with age: ~1-2/1000 in young adults to ~40/1000 in those ≥85 years
• 30-day mortality for hospitalized CAP: ~6% in-hospital, ~15% at 1 month
• 1-year mortality post-hospitalization approaches one-third; rises to ~50% for ICU-level CAP

• Age (strongest risk factor), male sex, smoking, poor dental hygiene, crowded living
• Comorbidities: malnutrition, alcohol use disorder, chronic immunosuppression, COPD, neurologic disease (impaired gag reflex)
• Medications: opioids, proton pump inhibitors, corticosteroids, other immunosuppressants
• Goldman-Cecil Medicine, p. 992

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4. Pathobiology

• Microaspiration - the primary mechanism for most bacterial pneumonias
• Inhalation of aerosols - e.g., TB, Legionella, anthrax
• Hematogenous spread - e.g., S. aureus right-sided endocarditis

• Mucociliary clearance
• Surfactant bacteriostasis
• Innate and adaptive immunity
• Cough reflex

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5. Etiology

Common Pathogens in CAP

Pneumococcus, H. influenzae, S. aureus, and gram-negative bacilli together cause up to 30% of cases; atypicals (Mycoplasma, Chlamydia, Legionella) cause <5% each. - Goldman-Cecil, p. 992

Epidemiologic Clues to Unusual Pathogens

• Goldman-Cecil Medicine, p. 996

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6. Clinical Manifestations

• Abrupt onset fever, rigors, productive cough (rust-colored sputum suggests pneumococcus)
• Pleuritic chest pain, dyspnea
• Signs of consolidation: dullness to percussion, bronchial breath sounds, egophony, increased tactile fremitus

• Gradual onset, dry cough, lower-grade fever
• "Walking pneumonia" - patient ambulatory
• Extrapulmonary features (headache, myalgia, rash, GI symptoms) common with Mycoplasma, Chlamydia, Legionella

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7. Diagnostic Approach

Step 1: Confirm the Diagnosis

• Chest X-ray (PA and lateral): New infiltrate is the radiographic cornerstone. Patterns:
  • Lobar consolidation - typical bacterial (pneumococcal)
  • Interstitial/bilateral - viral or atypical
  • Cavitation - S. aureus, anaerobes, gram-negatives, TB, fungi
  • CT chest: more sensitive; useful when CXR is equivocal, immunocompromised host, or suspected complication

Step 2: Assess Severity

• Score 0-1: Outpatient treatment
• Score 2: Consider inpatient
• Score ≥3: Hospitalize; consider ICU if ≥4-5

• 1 major criterion: Mechanical ventilation or septic shock requiring vasopressors
• OR ≥3 minor criteria: RR ≥30, PaO2/FiO2 ≤250, multilobar infiltrates, confusion, BUN ≥20 mg/dL, leukopenia (WBC <4000), thrombocytopenia (<100,000), hypothermia (<36°C), hypotension requiring aggressive fluid resuscitation

Step 3: Laboratory Investigations

• Fishman's, p. 2258

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8. Differential Diagnosis

• Acute heart failure (most common non-infectious mimic in elderly; check BNP)
• Pulmonary embolism with infarction (pleuritic pain + infiltrate)
• Lung cancer (post-obstructive pneumonia)
• ARDS (from any cause)
• Acute bronchitis (fever + cough but NO infiltrate)
• Organizing pneumonia (COP/BOOP) - responds to steroids not antibiotics
• Eosinophilic pneumonia, vasculitis, sarcoidosis

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9. Treatment

Outpatient CAP

Caution: Fluoroquinolones carry risks of tendinopathy, aortopathy, neuropathy, hypoglycemia, psychiatric effects, and may mask/delay TB diagnosis. Stewardship programs increasingly restrict their use. - Fishman's, p. 2258

Hospitalized CAP (Non-Severe)

Severe CAP / ICU

A 2025 network meta-analysis (PMID: 40602496) evaluated empiric antibiotic regimens for moderate-to-severe CAP. A 2025 meta-analysis in Lancet Respiratory Medicine (PMID: 39892408) provides updated data on predicting benefit from adjunctive corticosteroids.

Aspiration Pneumonia

• Anaerobic coverage is NOT routinely recommended in the absence of lung abscess or empyema (IDSA-ATS 2019 guideline update)
• Standard β-lactam coverage is generally adequate

Drug-Resistant Pathogens (MRSA / Pseudomonas)

• Previous MRSA infection/colonization
• Recurrent skin infections
• Severe disease

• Prior Pseudomonas infection/colonization
• Tracheostomy
• Bronchiectasis, cystic fibrosis
• Invasive respiratory support
• Very severe COPD

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10. Duration of Therapy

• Minimum 5 days for most uncomplicated CAP (IDSA-ATS)
• Clinical stability criteria for stopping: afebrile for ≥48h, HR <100, RR <24, SBP >90, SpO2 ≥90% on room air, tolerating oral intake, normal mental status
• Procalcitonin-guided therapy can safely reduce duration

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11. Supportive Care & Monitoring

• Supplemental oxygen to maintain SpO2 ≥94% (≥90% in COPD)
• IV fluids if dehydrated or hypotensive
• Chest physiotherapy, incentive spirometry
• DVT prophylaxis in hospitalized patients
• Monitor for complications: empyema (3-5%), atrial fibrillation and cardiac events (20-25% of hospitalized CAP), parapneumonic effusion
• Repeat CXR not needed in uncomplicated cases with good clinical response; radiographic clearance may lag 6-8 weeks in elderly

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12. Complications

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13. Prevention

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• Goldman-Cecil Medicine (International Edition, 2-Vol Set), Chapter 85 - Community-Acquired Pneumonia, pp. 992-996
• Fishman's Pulmonary Diseases and Disorders (2-Volume Set), CAP chapter, pp. 2255-2260
• IDSA/ATS Consensus Guidelines on the Management of CAP (2019 update)

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Tuberculosis - Clinical Approach

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Spectrum of TB Infection

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1. Definition & The Pathogen

• Rod-shaped, ~2-4 μm; obligate human pathogen, no environmental reservoir
• Doubles every 18-24 hours (extremely slow - cultures take weeks)
• "Waxy" cell envelope: contains mycolic acids, arabinogalactan, peptidoglycan - creates barrier to antibiotics and causes acid-fast staining (carbol fuchsin retained after acid wash)
• Facultative anaerobe; replicates intracellularly within macrophages
• Staining: Ziehl-Neelsen (ZN) stain - appears as red bacilli on blue background; Auramine-rhodamine fluorescent stain (more sensitive)

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2. Epidemiology & Transmission

• TB remains a major global health problem - ~10 million new cases/year worldwide
• Transmitted exclusively by aerosol from a person with active pulmonary/laryngeal TB
• Droplet nuclei (1-5 μm) remain suspended in air for hours; single-celled particles can reach the alveoli
• Risk of infection after exposure depends on: infectiousness of source case (smear-positive > smear-negative), duration and proximity of contact, ventilation of environment

A 2024 Cochrane meta-analysis (PMID: 39177079) confirmed diabetes as a significant independent risk factor for TB disease.

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3. Pathobiology

Primary Infection

1. Inhaled droplet nuclei reach alveoli → engulfed by alveolar macrophages
2. M. tuberculosis survives intracellularly by inhibiting phagosome-lysosome fusion
3. Bacilli replicate within macrophages → local spread → regional lymph node involvement
4. Ghon focus = initial parenchymal focus (usually mid-lung zone)
5. Ghon complex = Ghon focus + ipsilateral hilar lymphadenopathy
6. Ranke complex = calcified Ghon focus + calcified hilar node (healed primary TB)

Immune Response & Granuloma Formation

• T-lymphocytes (CD4+) arrive ~3-8 weeks after infection
• Macrophages and T cells form granulomas - organized structures that wall off bacilli
• Granuloma center: caseous necrosis (cheese-like), surrounded by epithelioid macrophages, Langhans giant cells, lymphocytes, fibrous capsule
• Tuberculin skin test (TST) and IGRA become positive ~3-8 weeks post-infection
• In most immunocompetent hosts, granulomas contain infection → latent TB infection (LTBI)

Reactivation

• Latent bacilli can survive for decades within granulomas
• When immunity wanes (see risk factors above), granulomas break down → reactivation TB
• Typically involves upper lobes (high O₂ tension favors bacterial growth)
• Caseous material liquefies → cavity formation → aerosolization → transmission

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4. Spectrum of TB Disease

• Goldman-Cecil Medicine, p. 3252

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5. Clinical Manifestations

Pulmonary TB (most common - ~85% of cases)

• Productive cough >3 weeks (most common; may be blood-stained → hemoptysis)
• Constitutional symptoms: fever (low-grade, often evening), night sweats, weight loss, anorexia, fatigue
• Chest pain (pleuritic if pleural involvement)

• Often minimal early
• Dullness to percussion, bronchial breath sounds over consolidation
• Amphoric breathing over cavities
• Post-tussive crepitations in upper lobes
• Signs of pleural effusion if present

Extrapulmonary TB

Immunologic/Hypersensitivity Manifestations

• Erythema nodosum - tender subcutaneous nodules (lower limbs)
• Erythema induratum (Bazin disease) - deeper vasculitic nodules, posterior calves
• Poncet disease - reactive arthritis + erythema nodosum
• TB-IRIS - immune reconstitution inflammatory syndrome (after starting ART in HIV-TB co-infection): paradoxical worsening; 5-50% incidence

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6. Diagnostic Approach

Step 1: Suspect TB

• Cough >2-3 weeks + any constitutional symptoms, especially in:
  • High-risk groups (HIV, immunosuppressed, contacts of known TB)
  • Immigrants from high-burden countries
  • Homeless, incarcerated populations

Step 2: Imaging

• Chest X-ray (PA view): first-line; upper lobe infiltrates/cavitation highly suggestive
• CT chest: more sensitive; detects early disease, miliary pattern, lymphadenopathy, cavities not visible on CXR

Step 3: Microbiological Confirmation

• CSF: lymphocytosis, elevated protein, low glucose, ADA elevated; ZN smear low sensitivity; Xpert MTB/RIF recommended
• Pleural fluid: exudate, lymphocyte-predominant; ADA >40 U/L strongly suggestive; pleural biopsy has higher yield
• Lymph node: FNA (cytology + ZN stain + culture) or excision biopsy (caseating granulomas)
• Urine: early morning urine x3 for AFB culture in genitourinary TB

Step 4: Immunological Tests (for LTBI)

• Intradermal injection of 5 TU PPD; read at 48-72 hours
• Measure induration (not erythema)

• QuantiFERON-TB Gold Plus or T-SPOT.TB
• Detects IFN-γ release to ESAT-6 and CFP-10 antigens (specific to M. tuberculosis complex, absent from BCG and most NTM)
• Advantages over TST: Not affected by BCG, single visit, more specific
• Preferred in BCG-vaccinated individuals; not validated in children <5 years
• Results: Positive / Negative / Indeterminate

Note: Both TST and IGRA test for immunological response to M. tuberculosis antigens - they cannot distinguish LTBI from active disease. A positive TST/IGRA in someone with symptoms should prompt workup for active disease.

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7. Treatment

A. Latent TB Infection (LTBI) - Preventive Therapy

In HIV-positive persons in high TB burden areas, 6 months of daily INH is complementary to ART regardless of IGRA result. - Goldman-Cecil, p. 3259

B. Active Pulmonary TB (Drug-Susceptible)

• 7-10 month continuation phase (total 9 months) for: cavitary disease with positive culture at 2 months, TB meningitis, bone/joint/spine TB, HIV-positive not on ART
• HIV on ART: Standard 6-month regimen effective; use daily dosing (not intermittent)

• WHO-recommended strategy where a health worker watches each dose being taken
• Improves adherence and treatment completion; detects adverse events early
• Especially important in resource-limited settings and for drug-resistant TB

C. Extrapulmonary TB Treatment Duration

D. Drug-Resistant Tuberculosis

• B - Bedaquiline
• Pa - Pretomanid
• L - Linezolid
• M - Moxifloxacin (if susceptible)
• Duration: 6 months

A 2025 systematic review (PMID: 39813501) confirms BPaLM as effective for MDR/RR-TB with acceptable safety profile.

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8. HIV-TB Co-infection

• HIV is the single most important risk factor for TB reactivation
• TB is the leading cause of death in people living with HIV worldwide
• All HIV patients should be screened for TB; all TB patients should be tested for HIV

• Start TB treatment first (before ART in most cases)
• Start ART within 2-8 weeks of TB treatment (earlier for severe immunosuppression CD4 <50)
• Drug interactions: Rifamycins are potent CYP3A4 inducers → reduce levels of many ARTs
  • Rifampicin + efavirenz: no dose adjustment
  • Rifampicin + dolutegravir: double dolutegravir dose (50 mg BD)
  • Rifabutin (fewer interactions) preferred with ritonavir-boosted protease inhibitors (half-dose rifabutin)
  • Avoid tenofovir alafenamide with rifamycins
• TB-IRIS: Watch for paradoxical worsening (fever, lymphadenopathy) after starting ART; treat with NSAIDs or corticosteroids if severe
• Continuation phase extended to 7 months (total 9 months) if not on ART at start of TB treatment

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9. Drug Monitoring & Adverse Effects

• INH: 300 mg OD or 900 mg 3x/week
• RIF: 600 mg OD (no change)
• PZA: 25-35 mg/kg 3x/week (after dialysis)
• EMB: 20-25 mg/kg 3x/week (after dialysis)

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10. Prevention & Public Health

• Patients with pulmonary TB are considered infectious until:
  • 2 weeks of effective treatment, AND
  • Clinical improvement, AND
  • 3 consecutive negative sputum smears (some guidelines require negative cultures)
• Smear-negative pulmonary TB is still potentially infectious (lower risk)

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11. Special Populations

Children

• More likely to develop primary progressive TB and extrapulmonary disease (especially miliary TB and meningitis)
• TST preferred; IGRA not validated <5 years
• Avoid ethambutol in young children unable to report visual symptoms

Pregnancy

• TB must be treated - risk of untreated TB to mother and fetus far exceeds drug risks
• 2HRZE/4HR is used; pyridoxine supplementation essential
• Streptomycin is contraindicated (ototoxicity to fetus)

Long-Term Outcomes

• A 2025 systematic review in Lancet Global Health (PMID: 40412395) found that post-TB lung function impairment is common even after successful treatment, with significant long-term morbidity including obstructive and restrictive patterns.

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• Goldman-Cecil Medicine (International Edition), Chapter 299 - Tuberculosis, pp. 3246-3262
• Fishman's Pulmonary Diseases and Disorders, CAP & TB sections
• Murray & Nadel's Textbook of Respiratory Medicine
• WHO Guidelines for Treatment of Drug-Susceptible and Drug-Resistant TB (2022)