How should I interpret a low total serum protein (6.8 g/dL) with low‑normal globulin fractions (α1‑0.3, α2‑0.7, β1‑0.5, β2‑0.4, γ‑0.7 g/dL), a positive antinuclear antibody screen, and a reactive Borrelia burgdorferi 93‑kD IgG antibody, and what are the recommended next steps?

Interpretation of Laboratory Findings and Recommended Next Steps

Your laboratory findings show a borderline-low total protein (6.8 g/dL) with proportionally reduced globulin fractions, a positive ANA, and reactive Borrelia burgdorferi 93-kD IgG antibody—this pattern most likely represents past or chronic Lyme disease with possible concurrent autoimmune disease, rather than primary immunodeficiency, because your albumin level (calculated from the globulin fractions) appears preserved.

Critical Diagnostic Distinction

The key to interpreting your low globulin levels is determining whether albumin and total protein are both reduced together. When total protein and albumin are both low, this strongly suggests secondary hypogammaglobulinemia from protein loss through the kidneys, gastrointestinal tract, or lymphatic system 1, 2, 3. In contrast, primary immunodeficiencies typically show normal albumin with isolated low immunoglobulins 2, 3.

Calculate Your Albumin Level

• Your globulin fractions sum to: 0.3 + 0.7 + 0.5 + 0.4 + 0.7 = 2.6 g/dL
• Estimated albumin = Total protein - Total globulins = 6.8 - 2.6 = 4.2 g/dL
• This albumin level (4.2 g/dL) is at the lower limit of normal (3.5-5.0 g/dL), suggesting possible protein loss rather than isolated immunoglobulin deficiency 1, 2

Immediate Evaluation Required

Rule Out Protein-Losing Conditions First

Before considering primary immunodeficiency, you must exclude secondary causes 2, 3:

Nephrotic syndrome evaluation:

• 24-hour urine protein collection 2, 3
• Spot urine protein-to-creatinine ratio 2
• Urinalysis for proteinuria 2

Protein-losing enteropathy evaluation:

• Assess for chronic diarrhea 2, 3
• Stool alpha-1 antitrypsin clearance if diarrhea present 2
• Consider intestinal imaging 2

Lymphatic disorder evaluation:

• Clinical assessment for lymphedema or lymphatic obstruction 2

Interpretation of the Borrelia burgdorferi 93-kD IgG Antibody

A reactive 93-kD IgG antibody indicates past or ongoing Borrelia burgdorferi infection and is highly specific for Lyme disease. The 93-kD protein is an immunodominant protoplasmic cylinder antigen recognized by sera from patients with both acute and chronic Lyme disease 4, 5. This antibody is present in patients with early and late infection and represents a sensitive and specific marker of Borrelia infection 4.

Critical Context for Lyme Disease Diagnosis

• This single band result is incomplete and cannot be interpreted in isolation 1
• A positive IgG Western immunoblot requires ≥5 of 10 bands (18,21-24,28,30,39,41,45,58,66, and 93 kDa) 1
• Interpreting fewer bands as positive leads to reduced specificity and potential misdiagnosis 1
• The 93-kD band alone, while highly specific, does not meet CDC criteria for a positive result 1

Required Next Steps for Lyme Disease Evaluation

You need complete two-tiered serologic testing 1:

1. First-tier EIA or IFA screening test
2. If positive or equivocal, reflex to full IgG Western immunoblot (not just the 93-kD band)
3. IgM Western immunoblot is unnecessary if symptoms have been present >30 days 1

Clinical correlation is essential:

• Document any history of tick exposure, erythema migrans rash, or symptoms consistent with Lyme disease (arthritis, neurologic symptoms, cardiac involvement) 1
• The IgG response generally persists for years after infection, so a positive result may indicate past rather than active disease 1

Interpretation of Positive ANA Screen

The positive ANA in conjunction with low globulins and possible protein loss raises concern for systemic lupus erythematosus (SLE) with lupus nephritis. Low complement levels (C3 and C4) together with hypoalbuminemia strongly suggest active lupus nephritis, particularly class V membranous disease 6.

Essential Complement Testing

Order complement C3 and C4 levels immediately 6:

• Simultaneous reduction of C3 and C4 indicates classic-pathway activation characteristic of SLE-related renal involvement 6
• Low C4 with normal C3 suggests alternative diagnoses 6
• Blood samples must be placed on ice or refrigerated immediately after collection to preserve labile complement components 1, 6

Additional SLE Workup Required

• Anti-double-stranded DNA antibodies to confirm SLE 6
• Antiphospholipid antibodies to assess thrombotic risk 6
• Complete urinalysis with microscopy 6
• Serum creatinine and estimated GFR 6

Consider Renal Biopsy

If significant proteinuria is present (>500 mg/24 hours or protein-to-creatinine ratio >0.5), renal biopsy is indicated to define the histologic class of lupus nephritis and guide immunosuppressive therapy 6.

Differential Diagnosis Considerations

Medication-Induced Hypogammaglobulinemia

Review your medication history for drugs that can cause reversible hypogammaglobulinemia 2, 3:

• Antiepileptic drugs: phenytoin, carbamazepine, valproic acid, zonisamide 2, 3
• Immunosuppressants: rituximab or other anti-CD20 therapies (21% develop IgG <5 g/L) 2
• Other agents: sulfasalazine, gold salts, penicillamine, hydroxychloroquine, NSAIDs 2, 3

Hematologic Malignancies

Exclude B-cell lymphomas or multiple myeloma, which can cause secondary hypogammaglobulinemia 2, 3:

• Complete blood count with differential 1
• Serum protein electrophoresis with immunofixation 1, 2
• Serum free light-chain assay (κ and λ) 1

Cryoglobulinemia

A membranoproliferative pattern with low complement levels raises suspicion for cryoglobulinemia, especially with hepatitis C infection 6. Test for cryoglobulins if hepatitis C risk factors are present.

Algorithmic Approach to Your Case

Step 1: Exclude Protein Loss (Most Likely Given Your Pattern)

1. Measure 24-hour urine protein or spot protein-to-creatinine ratio 2, 3
2. If proteinuria is present, proceed with SLE workup (complement levels, anti-dsDNA, renal biopsy) 6
3. If no proteinuria, assess for protein-losing enteropathy (stool alpha-1 antitrypsin) 2

Step 2: Complete Lyme Disease Evaluation

1. Obtain complete two-tiered serologic testing (EIA followed by full Western immunoblot) 1
2. Document clinical history of Lyme disease symptoms 1
3. If criteria are met for Lyme disease, determine whether treatment is indicated based on active versus past infection 1

Step 3: Complete SLE Workup

1. Measure complement C3 and C4 (with proper specimen handling) 6
2. Anti-dsDNA antibodies 6
3. Antiphospholipid antibodies 6
4. If lupus nephritis is confirmed, initiate immunosuppression with mycophenolate mofetil or cyclophosphamide plus glucocorticoids 6

Step 4: If Protein Loss Is Excluded, Evaluate for Primary Immunodeficiency

Only proceed with this workup if albumin and total protein are normal and protein-losing conditions are excluded 2, 3:

1. Quantitative immunoglobulin levels (IgG, IgA, IgM) 1, 2, 3
2. B-cell enumeration by flow cytometry to distinguish Common Variable Immunodeficiency (CVID) from agammaglobulinemia 2, 3
3. Specific antibody responses to protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal vaccine) 1, 2, 3
4. T-cell subset analysis to identify combined immunodeficiency 2, 3

Common Pitfalls to Avoid

• Do not diagnose primary immunodeficiency without first measuring albumin and total protein to exclude protein loss 1, 2, 3
• Do not interpret a single 93-kD band as diagnostic of active Lyme disease without complete two-tiered testing 1
• Do not order complement testing without ensuring proper specimen handling (immediate cooling) 1, 6
• Do not overlook medication-induced hypogammaglobulinemia by failing to obtain a complete medication history 2, 3
• Do not delay renal biopsy if lupus nephritis is suspected with significant proteinuria 6

Urgent Management Considerations

If your IgG level is ultimately found to be <300 mg/dL, you are at high risk for life-threatening infections by encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) and require urgent immunoglobulin replacement therapy 2, 3. However, given your borderline-low total protein with preserved albumin, this scenario is less likely than protein loss or autoimmune disease.