Influenza

1. Virology and Classification

• Type A - most clinically important; undergoes both antigenic drift and shift; classified by surface glycoproteins hemagglutinin (H1-H18) and neuraminidase (N1-N11)
• Type B - predominantly human; undergoes antigenic drift but NOT shift; two circulating lineages (Victoria and Yamagata)
• Type C - rare; causes mild intermittent illness

Genome Segments and Key Proteins

• Medical Microbiology 9e, p. 555 (Segment/Protein table)

2. Antigenic Variation - The Key to Epidemics

Historical Pandemics from Antigenic Shift

• Harrison's Principles of Internal Medicine 22E, p. 1589; Medical Microbiology 9e, p. 555

3. Pathogenesis

Time Course of Infection

4. Epidemiology

Annual US Burden (2010-2023)

5. Clinical Features

• Abrupt onset high fever
• Throbbing headache, photophobia
• Severe myalgia and malaise
• Sore throat, substernal soreness
• Non-productive cough
• Disabling fatigue

• Children: fever, rhinitis, pharyngitis, vomiting, diarrhea
• Elderly: high fever, nasal obstruction, lassitude, diarrhea

6. Complications

1. Primary influenza pneumonia - direct viral pneumonitis; persistent high fever and dyspnea >3-4 days; more common in elderly, immunocompromised, and pregnant women (but can affect young adults)
2. Secondary bacterial pneumonia - most commonly Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae; follows initial improvement then relapse
3. Mixed viral-bacterial pneumonia

• Myocarditis (influenza A and B are established causes)
• Encephalitis/neurologic complications
• Rhabdomyolysis
• Exacerbation of COPD, asthma, heart failure

7. High-Risk Groups (Priority for Vaccination and Treatment)

• Adults ≥65 years
• Children 6 months - 5 years
• Pregnant women (and up to 2 weeks postpartum)
• Residents of nursing homes and long-term care facilities
• Persons with chronic medical conditions (cardiac, pulmonary, renal, hepatic, neurologic, hematologic, metabolic disorders including diabetes)
• Immunocompromised individuals (HIV, chemotherapy, steroids)
• Morbidly obese (BMI ≥40)
• American Indian/Alaska Native populations
• Health care personnel
• Harrison's Principles of Internal Medicine 22E, Table 206-2

8. Diagnosis

• Results in ~15 minutes
• Sensitivity: ~50-70%; specificity: ~90-95%
• A negative test does NOT exclude influenza when the patient has compatible symptoms during active community circulation

9. Treatment - Antiviral Drugs

• All hospitalized patients: start antivirals (oseltamivir) as soon as possible regardless of time from onset
• High-risk outpatients: treat when influenza is suspected/confirmed
• Otherwise healthy outpatients: consider if within 48 hours of symptom onset
• Treatment should begin as early as possible; do not withhold in severely ill patients even if >48 hours have elapsed
• Harrison's Principles of Internal Medicine 22E, p. 1590; Tintinalli's Emergency Medicine; Creasy & Resnik's Maternal-Fetal Medicine

10. Vaccination

Types of Vaccines

• Inactivated influenza vaccine (IIV) - licensed >60 years; injected; safe in pregnancy
• Recombinant influenza vaccine (RIV) - FDA-approved 2017; avoids egg-adaptation issues
• Live attenuated influenza vaccine (LAIV) - intranasal; preferred in children (ages 2-49 years); not for pregnant women or immunocompromised
• High-dose and adjuvanted vaccines - preferred for adults ≥65 years; superior immunogenicity and effectiveness vs. standard dose

Effectiveness

Vaccine Safety Notes

• Common: local injection site reactions
• Rare: Guillain-Barré syndrome (identified in 1976 vaccine; risk very small)
• Adjuvanted vaccines: more local pain/erythema
• LAIV: avoid in asthma/immunocompromised patients

• Harrison's Principles of Internal Medicine 22E, pp. 1589-1591

11. Prevention Beyond Vaccination

• Hand hygiene and respiratory etiquette (cough/sneeze into elbow)
• Droplet/contact precautions in healthcare settings (airborne precautions for aerosol-generating procedures)
• Post-exposure chemoprophylaxis with oseltamivir or zanamivir (75 mg oseltamivir once daily for 10 days) for high-risk contacts during outbreaks
• Avoid contact with sick individuals during the infectious period (1 day before to ~5-7 days after symptom onset)

Pneumonia

1. Definition and Overview

• Annual incidence: 16-23 per 1,000 adults
• ~30% of CAP patients require hospitalization; mortality among outpatients <5%, rising to 12-40% in hospitalized patients
• Overall annual cost: ~$17 billion (US)

2. Classification

3. Etiology and Common Pathogens

Community-Acquired Pneumonia (CAP)

• Streptococcus pneumoniae (pneumococcus) - most common proven cause; accounts for ~2/3 of CAP with positive blood cultures
• Haemophilus influenzae - especially in COPD/smokers
• Staphylococcus aureus - especially post-influenza, cavitary/necrotizing pneumonia
• Klebsiella pneumoniae - especially in alcoholics
• Moraxella catarrhalis - COPD

• Mycoplasma pneumoniae - younger patients, community outbreaks
• Chlamydophila pneumoniae - insidious onset, mild disease
• Legionella spp. - hotel/cruise ship exposure, water systems; can be severe

Epidemiologic Clues to Pathogen (Harrison's Table 131-2)

Hospital-Acquired (HAP) and Ventilator-Associated (VAP) Pneumonia

• S. aureus (including MRSA)
• Pseudomonas aeruginosa
• Gram-negative enteric bacilli (Klebsiella, Enterobacter, E. coli, Acinetobacter)

• IV antibiotic use within prior 90 days
• Septic shock at time of VAP
• ARDS preceding VAP
• ≥5 days in hospital before VAP onset
• Acute renal replacement therapy before VAP

4. Pathogenesis and Pathophysiology

1. Microaspiration of oropharyngeal secretions (most common)
2. Inhalation of aerosolized droplets
3. Hematogenous spread

1. Congestion - vascular engorgement, edema
2. Red hepatization - alveoli fill with red blood cells, fibrin, PMNs
3. Grey hepatization - RBCs lyse; fibrin, PMNs persist
4. Resolution - enzymatic digestion, macrophage clearance

5. Clinical Features

Typical (Bacterial) Pneumonia

• Abrupt onset with high fever, rigors/chills
• Productive cough (purulent or rust-colored sputum in pneumococcal pneumonia)
• Pleuritic chest pain
• Dyspnea
• Physical exam: decreased breath sounds, dullness to percussion, bronchial breathing, egophony, tactile fremitus over consolidation
• WBC typically >15,000/mm³ with neutrophilia

Atypical Pneumonia

• Gradual onset over days
• Low-grade fever, less impressive constitutional symptoms (the "walking pneumonia" pattern)
• Dry, non-productive cough
• Extrapulmonary features common (headache, rash, arthralgias - especially Mycoplasma)
• Often younger patients
• Chest X-ray may appear worse than symptoms suggest

Age-specific features:

• Children: Tachypnea is the earliest and most sensitive sign; intercostal retractions; viral pneumonias appear less toxic (low-grade fever, wheeze); bacterial pneumonias appear more acutely ill with high fever
• Elderly: May present atypically - confusion, falls, functional decline without classic respiratory symptoms; fever may be absent

6. Diagnosis

Clinical Diagnosis

• New respiratory symptoms (cough, dyspnea, chest pain)
• Fever
• New infiltrate on chest imaging
• Supporting exam findings

Imaging

• Chest X-ray - standard initial investigation
  • Bacterial (typical): lobar/segmental consolidation, air bronchograms, alveolar infiltrates
  • Atypical: bilateral interstitial or patchy infiltrates, often perihilar
  • Viral: bilateral interstitial pattern, hyperinflation
  • Note: CXR findings typically lag the clinical course by 1-2 days and can be normal on day 1
  • Parapneumonic pleural effusions may be present
• CT chest - more sensitive; useful when CXR inconclusive or complications suspected (abscess, empyema)

Laboratory

• CBC with differential (leukocytosis with left shift in bacterial; leukopenia can indicate severe disease)
• Metabolic panel (urea/BUN - part of CURB-65 scoring)
• Sputum Gram stain and culture - low yield but useful if obtained correctly before antibiotics
• Blood cultures - recommended before antibiotics in hospitalized patients (quality indicator); bacteremia in ~15-20% of pneumococcal pneumonia
• Urinary antigen tests: Legionella (serogroup 1) and S. pneumoniae - rapid, highly specific
• Cold agglutinins: positive in Mycoplasma pneumoniae (sensitivity ~50%)
• Procalcitonin - elevated in bacterial infection; useful to guide antibiotic duration
• RT-PCR/molecular panels - highly sensitive for respiratory viruses, Mycoplasma, Legionella; increasingly used

When to perform invasive procedures

• Immunocompromised patients
• Failure to respond to empiric therapy
• VAP diagnosis
• Suspected unusual pathogens

7. Severity Assessment and Site of Care

CURB-65 Score (preferred for simplicity)

• Score 0-1: Low risk - outpatient treatment
• Score 2: Moderate risk - consider short inpatient admission
• Score ≥3: High risk - hospital admission; consider ICU if score ≥4-5
• PSI class V and CURB-65 ≥3 may need ICU

Important: Scoring tools guide but do not replace clinical judgment. Also consider: ability to maintain oral intake, comorbidities, living situation, compliance, oxygenation (pulse oximetry), and social support.

Indications for hospitalization

• Failure to respond to or tolerate oral antibiotics
• Significant hypoxemia (SaO₂ <90% on room air)
• Multilobar consolidation
• Parapneumonic empyema
• Immunosuppression
• Lung abscess or pneumatocele
• Underlying cardiopulmonary disease
• Age extremes (infants <2 months, elderly)

ICU admission criteria (ATS/IDSA major criteria)

• Septic shock requiring vasopressors
• Acute respiratory failure requiring mechanical ventilation

8. Treatment

Outpatient CAP (low severity, no comorbidities)

Inpatient CAP (non-ICU)

• Beta-lactam (ampicillin-sulbactam, ceftriaxone, or cefotaxime) + macrolide, OR
• Respiratory fluoroquinolone monotherapy

Severe CAP (ICU)

• Beta-lactam + macrolide, OR beta-lactam + respiratory fluoroquinolone
• Add MRSA coverage (vancomycin or linezolid) if: cavitary pneumonia, post-influenza, necrotizing pneumonia, gram-positive cocci on Gram stain
• Add P. aeruginosa coverage (anti-pseudomonal beta-lactam) if: structural lung disease (bronchiectasis), recent broad-spectrum antibiotics, prior Pseudomonas isolation

HAP/VAP Treatment

• Cover MSSA with: piperacillin-tazobactam, cefepime, meropenem, imipenem, or levofloxacin
• Add vancomycin or linezolid if MRSA rate >10-20% or risk factors present
• Use two antipseudomonal agents from different classes if MDR risk factors present or gram-negative resistance rates >10%
• De-escalate once culture/sensitivity results are available

Aspiration Pneumonia

• Routine anaerobic coverage is NOT necessary unless: poor dentition, lung abscess, or necrotizing pneumonia
• If community-acquired: amoxicillin-clavulanate or clindamycin
• If hospital-acquired: piperacillin-tazobactam or carbapenem

Duration of Therapy

• Minimum 5 days for CAP; continue at least 48-72 hours beyond clinical stability (afebrile, improved respiratory status)
• Atypical organisms (Legionella, Mycoplasma): typically 10-14 days (fluoroquinolone or macrolide)
• HAP/VAP: 7 days if clinically responding; shorter courses supported by evidence

9. Complications

10. Prevention

Vaccination (cornerstone of prevention)

• PCV20 (20-valent pneumococcal conjugate vaccine) - recommended for all adults ≥65 and high-risk adults ≥19 years (immunocompromised, chronic lung/liver/kidney/heart disease, diabetes, CSF leak, cochlear implants, cigarette smokers)
• PCV15 + PPSV23 sequence is an alternative for adults ≥65
• Re-vaccination with PPSV23 after 10 years if first dose given before age 65

General measures

• Smoking cessation (smoking is a major risk factor for pneumococcal pneumonia and impairs mucociliary clearance)
• Hand hygiene
• Avoid aspiration risk (upright positioning after meals, good oral hygiene)
• Appropriate infection control in hospitals (hand hygiene, care bundles for VAP prevention including head-of-bed elevation 30-45°, oral chlorhexidine, subglottic suctioning, daily sedation interruption)

11. Differential Diagnosis

• Pulmonary embolism (most common cause of "atypical pneumonia" - always consider)
• Congestive heart failure with pulmonary edema
• Hypersensitivity pneumonitis
• Bronchiolitis obliterans organizing pneumonia (BOOP/COP)
• Acute eosinophilic pneumonia
• Pulmonary hemorrhage (Goodpasture's syndrome, mitral stenosis)
• Foreign body aspiration
• Connective tissue diseases (lupus pneumonitis, RA-associated ILD)
• Lung malignancy

Recent Evidence (2025-2026)