What is the approach for a patient with negative IgM and low IgG levels for Bordetella (B.) pertussis?

Approach to Negative IgM with Low IgG for Bordetella pertussis

When IgM is negative but IgG is low in suspected pertussis, focus on IgG and IgA antibody testing using paired sera to demonstrate a fourfold rise, as IgM is not a reliable marker for pertussis diagnosis and IgG/IgA provide superior diagnostic accuracy. 1

Diagnostic Strategy for Negative IgM

Why IgM Testing is Not Recommended

• IgM antibodies are not part of the standard serologic criteria for pertussis diagnosis - the ACCP guidelines specifically recommend measuring IgG and IgA antibodies to pertussis toxin (PT) or filamentous hemagglutinin (FHA), with no mention of IgM as a diagnostic tool 1

• IgM antibodies show age-dependent variability and are negatively correlated with age (r = -0.37), with highest titers in schoolchildren aged 6-15 years, making interpretation problematic in adults 2

• Up to 39.5% of healthy donors in certain age groups (11-15 years) can be interpreted as pertussis-positive or indeterminate based on IgM titers alone, severely limiting diagnostic specificity 2

Proper Serologic Approach with Low IgG

Order paired acute and convalescent sera to demonstrate a fourfold increase in IgG or IgA antibodies to PT or FHA - this is the most generally accepted serologic criterion for diagnosis 1

• Collect the first serum sample within 2 weeks of cough onset 1
• Collect the second sample 3-4 weeks later 1
• The reported specificity and sensitivity of this paired IgG testing are 99% and 63%, respectively, when used for documenting pertussis outbreaks 1

When Single IgG Testing May Be Sufficient

• A single serum specimen showing high IgG titers (>27 IU/mL, which is 3 times the upper limit of normal) compared to reference values is highly suggestive of recent pertussis infection when there is a compatible clinical picture 3

• IgG levels ≥70 arbitrary units in oral fluid correlate with seropositivity and can detect pertussis with 79.7% sensitivity and 96.6% specificity in children with chronic cough 4

• Recent vaccination within 3 years prior to testing does not significantly increase IgG levels, so elevated IgG likely represents infection rather than vaccine response 3

Critical Diagnostic Considerations

Culture and PCR Remain Gold Standard Early in Disease

• Nasopharyngeal culture is the only certain way to make a definitive diagnosis - order a nasopharyngeal aspirate or Dacron swab for culture when pertussis is suspected 1

• Culture sensitivity is only 25-50%, but isolation of B. pertussis provides definitive confirmation 1

• PCR has 80-100% sensitivity but is not recommended for routine clinical testing as there is no universally accepted, validated technique 1

Timing Affects Test Selection

• Cultures and PCR are most reliable in the first 2-3 weeks of illness (catarrhal phase) 1

• Serology becomes more useful after 2-3 weeks when culture/PCR sensitivity declines - this is when paired sera or single high-titer IgG testing is most valuable 1, 3

• In one study, 50% of IgG-positive patients had positive PCR when both were performed, but IgG values were similar regardless of PCR result, suggesting IgG can establish diagnosis when PCR is negative late in disease 3

Clinical Context for Low IgG Interpretation

Consider Underlying Immunodeficiency

If IgG levels are globally low (not just pertussis-specific antibodies), evaluate for:

• Common Variable Immunodeficiency (CVID) - suspect in patients over 4 years old with total IgG below 450-500 mg/dL, low IgA, and impaired antibody responses 5

• Secondary causes - medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs), protein loss (GI, renal, lymphatic), B-cell lymphomas, HIV, or post-transplant status 5

• Measure total serum IgG, IgA, and IgM levels as part of the minimum bundle of aetiological tests 1

Specific Antibody Response Testing

• Measuring specific antibody responses to vaccines is essential when evaluating low IgG levels, as total IgG levels alone do not predict antibody production capacity 5

• Normal total IgG does not exclude IgG subclass deficiency or specific polysaccharide antibody deficiency 1, 5

Treatment Implications

Initiate Treatment Based on Clinical Suspicion

• Begin macrolide therapy (erythromycin 1-2 g/day for adults, azithromycin preferred for better tolerability) as soon as pertussis is suspected - do not delay for serologic confirmation 1

• Early therapy during the catarrhal phase (first 2 weeks) rapidly clears B. pertussis and decreases coughing paroxysms 1

• Isolate patients at home/away from work or school for 5 days after starting antibiotics 1

Common Pitfalls to Avoid

• Do not rely on IgM testing for pertussis diagnosis - it is not validated and has poor age-adjusted specificity 2

• Do not wait for paired sera results before treating - clinical suspicion with compatible symptoms (cough >2 weeks with paroxysms, post-tussive vomiting, or inspiratory whoop) warrants empiric treatment 1

• Do not assume low pertussis-specific IgG means no infection - it may indicate testing too early in the disease course or underlying immunodeficiency affecting antibody production 1, 5

• Patients with posttussive syncope are much more likely to have pertussis and should be treated empirically while awaiting confirmatory testing 3