How do you differentiate infection from autoimmune inflammation?

Differentiating Infection from Autoimmune Inflammation

Laboratory testing for inflammatory markers, autoantibodies, and specific microbial studies combined with clinical context is the most reliable approach to differentiate infection from autoimmune inflammation. 1

Key Diagnostic Differences

Clinical Presentation

• Infection:

  • Typically acute or subacute onset
  • Often accompanied by fever and specific localizing symptoms
  • May have identifiable exposure history
  • Usually responds to antimicrobial therapy
  • Tends to be monophasic unless inadequately treated

• Autoimmune Inflammation:

  • Can be acute, subacute, or chronic (>3 months)
  • Often polysyndromic presentation (multiple organ systems)
  • May have personal or family history of autoimmune disorders
  • Responds to immunosuppressive therapy
  • Can have relapsing-remitting or progressive course

Laboratory Evaluation

First-Line Tests

1. Complete Blood Count:

   • Neutrophilia often predominates in bacterial infections
   • Lymphocytosis may be seen in viral infections
   • Variable patterns in autoimmune conditions

2. Inflammatory Markers:

   • CRP and ESR elevated in both conditions
   • Procalcitonin often elevated in bacterial infections but not typically in autoimmune conditions
   • SAA (Serum Amyloid A) and S100 proteins may be used as additional inflammatory markers 1

3. Autoantibody Testing:

   • Positive ANA, RF, specific autoantibodies (anti-dsDNA, ENA panel) suggest autoimmune etiology 2
   • Glycosylated ferritin <20% highly specific for adult-onset Still's disease 1
   • IL-18 levels >5,000 pg/mL highly suggestive of autoinflammatory conditions rather than infection 1

4. Microbiological Studies:

   • Blood cultures, specific PCR tests, and serologies for suspected pathogens
   • CSF analysis in suspected CNS involvement

Cerebrospinal Fluid Analysis (when CNS involvement suspected)

• Infection:

  • Often shows neutrophilic pleocytosis (bacterial)
  • Lymphocytic pleocytosis (viral, TB)
  • Positive cultures or PCR for pathogens
  • Low glucose, high protein

• Autoimmune:

  • Lymphocytic pleocytosis
  • Elevated IgG index and oligoclonal bands
  • Positive neuronal autoantibodies
  • Normal glucose, mildly elevated protein 1

Imaging

• MRI:

  • Certain patterns more suggestive of autoimmune etiology (e.g., bilateral limbic involvement in autoimmune encephalitis)
  • Gradient echo sequence more common in herpetic encephalitis than autoimmune encephalitis 1
  • Radial perivascular enhancement suggests autoimmune GFAP astrocytopathy 1

• FDG-PET:

  • Can help identify focal or multifocal brain abnormalities when MRI is negative
  • Often more sensitive than MRI in autoimmune encephalitis 1

Diagnostic Algorithm

1. Assess clinical presentation and risk factors:

   • Duration of symptoms (acute vs. chronic)
   • Pattern of organ involvement (focal vs. multisystem)
   • History of autoimmune disorders or recent infections
   • Immunocompromised status

2. Initial laboratory workup:

   • CBC with differential
   • CRP, ESR, procalcitonin
   • Basic autoantibody panel (ANA, RF)
   • Blood cultures if fever present
   • Targeted microbiological studies based on symptoms

3. If CNS involvement:

   • Brain MRI with and without contrast
   • EEG (to rule out subclinical seizures)
   • Lumbar puncture with CSF analysis for:
     • Cell count and differential
     • Protein and glucose
     • Neuronal autoantibodies
     • Infectious studies (cultures, PCR panels) 1

4. If initial tests inconclusive:

   • Expanded autoantibody testing
   • FDG-PET imaging
   • Tissue biopsy of affected organ when feasible

Special Considerations

Overlapping Presentations

Some conditions can present with features of both infection and autoimmune inflammation:

1. Post-infectious autoimmunity:

   • Autoimmune encephalitis following HSV encephalitis
   • Guillain-Barré syndrome following Campylobacter infection
   • Reactive arthritis following enteric or urogenital infections 3

2. Drug-induced autoimmunity:

   • Certain medications can trigger autoimmune phenomena that mimic infection 1

3. Autoinflammatory syndromes:

   • Periodic fever syndromes can mimic recurrent infections
   • Require genetic testing for definitive diagnosis 2

Pregnancy and Postpartum Period

Autoimmune conditions may improve during pregnancy but frequently flare postpartum. Consider autoimmune etiology in postpartum liver dysfunction, especially with hypergammaglobulinemia 1.

Pitfalls to Avoid

1. Assuming single etiology:

   • Infection and autoimmunity can coexist
   • Infections can trigger autoimmune responses
   • Immunosuppressive therapy for autoimmune conditions increases risk of opportunistic infections 4

2. Overreliance on single tests:

   • False positive autoantibodies can occur in infections
   • False negative cultures in partially treated infections

3. Failure to consider immunosuppression:

   • Secondary immunodeficiency can mimic primary autoimmune disorders 1
   • Always evaluate for underlying immunodeficiency in recurrent infections

When to Suspect Both Processes

Consider concurrent infection and autoimmune processes when:

1. Partial response to antimicrobials or immunosuppressants
2. Worsening despite appropriate therapy for one condition
3. Laboratory evidence supporting both processes
4. Known autoimmune disease with new, atypical symptoms

Remember that immunosuppressive therapy for autoimmune conditions increases risk of serious infections, including opportunistic pathogens. A thorough diagnostic workup is essential before initiating immunosuppression 4.