What is the differential diagnosis of acute pneumonia?

Differential Diagnosis of Acute Pneumonia

The differential diagnosis of acute pneumonia must systematically distinguish infectious from non-infectious causes, identify specific pathogens when possible, and recognize conditions that mimic pneumonia radiographically and clinically.

Primary Infectious Etiologies

Bacterial Pathogens

Typical Bacterial Pneumonia:

• Streptococcus pneumoniae remains the most common identified bacterial pathogen, accounting for approximately 15% of cases with identified etiology 1
• Haemophilus influenzae 2
• Staphylococcus aureus, particularly in patients failing initial empiric therapy or with risk factors 2
• Enteric gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Enterobacter species), especially in patients with cardiopulmonary disease or nursing home residence 2
• Drug-resistant Streptococcus pneumoniae (DRSP), particularly in patients with recent antibiotic exposure 2

Atypical Bacterial Pneumonia:

• Mycoplasma pneumoniae accounts for 13-37% of outpatient pneumonia when serologic testing is performed 3
• Chlamydophila pneumoniae (formerly Chlamydia pneumoniae) occurs in up to 17% of outpatients with community-acquired pneumonia 3
• Legionella species, with rates varying from 0.7% to 13% in outpatients and higher rates in severe pneumonia requiring ICU admission 2, 3
• Mixed infections involving both typical and atypical pathogens occur in 3-40% of cases 2, 3

Aspiration-Related Pneumonia:

• Anaerobic oral flora in patients with risk factors including alcoholism, injection drug use, nursing home residency, neurologic illness, or impaired consciousness 2
• Mixed aerobic and anaerobic bacteria 2

Viral Pathogens

Common Respiratory Viruses:

• Influenza A and B viruses 2
• SARS-CoV-2 (COVID-19), which should be tested in all patients when circulating in the community 1
• Respiratory syncytial virus 2
• Parainfluenza viruses 1-3 2
• Adenovirus 2
• Human metapneumovirus 2
• Coronavirus (non-COVID-19 strains) 2
• Rhinovirus 2
• Bocavirus 2

Viruses are identified in up to 40% of hospitalized patients with identified pneumonia etiology 1

Unusual and Opportunistic Pathogens

Consider when clinical and radiographic findings persist or in specific epidemiological contexts:

• Mycobacterium tuberculosis, particularly with chronic pneumonia presentation, known exposure, or epidemiological risk factors 2
• Endemic fungi: Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis 2
• Pneumocystis jirovecii (formerly P. carinii) in immunocompromised patients 2
• Nocardia species, especially in relapsing pneumonia 2

Zoonotic and Travel-Related Pathogens:

• Coxiella burnetii (Q fever) following exposure to parturient cats, cattle, sheep, or goats 2
• Francisella tularensis (tularemia) with exposure to infected rabbits and ticks 2
• Chlamydophila psittaci (psittacosis) after avian exposure 2
• Yersinia pestis (plague) or Leptospira species with rat exposure 2
• Burkholderia pseudomallei with travel to Southeast Asia 2
• Paragonimiasis with travel to Asia, Africa, or Central/South America 2
• Pasteurella multocida, Bacillus anthracis, Actinomyces israelii, Rhodococcus equi 2

Resistant Organisms Requiring Specific Risk Factors:

• Pseudomonas aeruginosa should only be considered with specific risk factors including chronic or prolonged broad-spectrum antibiotic therapy (≥7 days within the past month) 2

Non-Infectious Mimics of Pneumonia

Malignancy

• Lung cancer, particularly in older smokers, can present with radiographic findings mimicking pneumonia 2
• Lymphoma 2

Inflammatory and Autoimmune Conditions

• Connective tissue disease-associated interstitial lung disease (CTD-ILD), particularly rheumatoid arthritis, myositis syndromes, and anti-synthetase syndromes 2
• Vasculitis 2
• Dermatomyositis 2
• Organizing pneumonia (cryptogenic organizing pneumonia/COP) 2
• Sarcoidosis 2

Hypersensitivity and Drug Reactions

• Hypersensitivity pneumonitis (acute, subacute, or chronic) 2
• Drug-induced pneumonitis 2

Interstitial Lung Diseases

• Idiopathic pulmonary fibrosis with acute exacerbation 2
• Nonspecific interstitial pneumonia (NSIP) 2
• Acute interstitial pneumonia (AIP) 2
• Desquamative interstitial pneumonia (DIP) 2
• Respiratory bronchiolitis with interstitial lung disease (RBILD) 2
• Lymphoid interstitial pneumonia (LIP) 2

Other Non-Infectious Conditions

• Acute eosinophilic pneumonia (eosinophil differential count >25% on BAL is virtually diagnostic) 2
• Diffuse alveolar hemorrhage 2
• Atelectasis, which cannot be reliably distinguished from pneumonia by clinical or radiographic features alone 4
• Pulmonary edema/congestive heart failure 2

Critical Diagnostic Approach

When Standard Therapy Fails

If the patient is not clinically stable by Day 3 or shows no response after 7 days of therapy, re-evaluate for:

1. Inadequate antimicrobial selection: The organism may be resistant to initial empiric therapy, particularly S. aureus not covered by standard regimens 2

2. Drug-resistant pathogens: DRSP in patients without identified risk factors, or P. aeruginosa in patients with risk factors 2

3. Viral etiology: The infection may be caused by an agent not responsive to antimicrobials 2

4. Unusual pathogens: Consider tuberculosis, endemic fungal pneumonia, P. jirovecii, or nocardiosis, especially with chronic or relapsing presentations 2

5. Non-infectious etiology: Malignancy, organizing pneumonia, vasculitis, or other inflammatory conditions 2

Key Diagnostic Limitations

• Even with comprehensive diagnostic testing including invasive procedures, no pathogen is identified in 40-50% of outpatients and approximately 50% of hospitalized patients with pneumonia 3, 5
• Clinical features, physical examination, laboratory tests, and chest radiography cannot reliably differentiate typical from atypical pneumonia or establish specific etiologic diagnosis 3, 6
• Host factors (age, comorbidities) dominate clinical presentation more than the specific pathogen 3

Common Pitfalls to Avoid

• Do not delay empiric antibiotics while attempting etiologic diagnosis, as mortality increases with delayed first antibiotic dose 6
• Do not rely on clinical features alone to distinguish between typical and atypical pneumonia; empiric therapy should cover both 3, 6
• Do not overlook mixed infections involving both bacterial and atypical pathogens, which occur in 3-40% of cases 2, 3
• Do not forget to test for influenza and COVID-19 when these viruses are circulating in the community, as their diagnosis affects treatment and infection prevention strategies 1
• Do not treat colonization as pneumonia in ventilated patients; obtain respiratory cultures before starting antibiotics and reassess if cultures are sterile at 48-72 hours 4