In a patient being evaluated for suspected Lyme disease with an elevated lymphocyte percentage (~41%) and a mildly increased mean platelet volume (10.5 fL), what is the appropriate diagnostic work‑up and initial management?

Diagnostic Work-Up for Suspected Lyme Disease with Lymphocytosis and Elevated Mean Platelet Volume

Immediate Priority: Rule Out Tick-Borne Rickettsial Diseases

The laboratory findings of relative lymphocytosis (41.1%) and elevated mean platelet volume (10.5 fL) are atypical for Lyme disease but raise concern for co-infection with tick-borne rickettsial diseases, particularly ehrlichiosis or anaplasmosis, which require urgent empiric treatment with doxycycline. 1

Critical Distinction in Laboratory Patterns

• Lyme disease typically does NOT cause significant lymphocytosis in peripheral blood; when present, lymphocytosis suggests either co-infection with tick-borne rickettsial pathogens or an alternative diagnosis 1

• Ehrlichiosis and anaplasmosis characteristically cause leukopenia with neutropenia and thrombocytopenia, not lymphocytosis, making this presentation somewhat atypical but not exclusionary 1, 2

• Elevated mean platelet volume (MPV >10 fL) indicates platelet activation and is associated with thrombotic events and inflammatory states, which can occur in severe tick-borne infections 3, 4

Essential Immediate Laboratory Testing

Complete Blood Count Analysis

• Obtain absolute neutrophil count, absolute lymphocyte count, and platelet count to determine if the lymphocytosis is relative (due to neutropenia) or absolute 1
• Examine peripheral blood smear manually for morulae within leukocytes (monocytes, neutrophils, or lymphocytes), which are diagnostic of ehrlichiosis or anaplasmosis in 1-20% of cases 1
• Look for atypical lymphocytes, which may be present in tularemia and other tick-borne infections 1

Coagulation and Inflammatory Markers

• Measure D-dimer, PT/INR, fibrinogen, and triglycerides to screen for disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis (HLH), both life-threatening complications of tick-borne infections 5, 6
• Obtain ferritin level as hyperferritinemia (>500 μg/L) is a key diagnostic criterion for HLH, which can be triggered by ehrlichiosis 5

Hepatic Function

• Check AST, ALT, and bilirubin as elevated transaminases are characteristic of ehrlichiosis, anaplasmosis, and tularemia 1

Tick-Borne Pathogen Testing

• Order Ehrlichia and Anaplasma PCR and serology immediately if there is any history of tick exposure or outdoor activity in endemic areas (April-September peak season) 5, 2, 6
• Proceed with Lyme disease two-tier testing (ELISA followed by Western blot if positive) as the primary indication for the work-up 1
• Consider Babesia smear and PCR as co-infection occurs in up to 20% of Lyme disease cases in endemic areas 1

Blood Cultures

• Obtain blood cultures to exclude bacterial sepsis, which can present similarly with fever and cytopenias 5, 6

Empiric Treatment Decision Algorithm

Start Doxycycline Immediately If:

• History of tick bite or outdoor exposure in endemic areas during April-September 2, 6
• Fever with thrombocytopenia and normal or low-normal WBC count (even without confirmed diagnosis) 6
• Any evidence of morulae on peripheral smear 1
• Elevated transaminases with fever and cytopenias 1

Dosing: Doxycycline 100 mg orally or IV twice daily for 7-14 days 5, 2

Critical Pitfall to Avoid

Do NOT wait for serologic confirmation before starting doxycycline in suspected tick-borne rickettsial disease, as IgM and IgG antibodies are typically not detectable before the second week of illness, and 50% of Rocky Mountain spotted fever deaths occur within 9 days of symptom onset 1

Monitoring for Hemophagocytic Lymphohistiocytosis

HLH-2004 Diagnostic Criteria (≥5 of 8 Required)

• Fever >38.5°C 5
• Splenomegaly 5
• Cytopenias affecting ≥2 lineages (hemoglobin <9 g/dL, platelets <100 × 10⁹/L, neutrophils <1.0 × 10⁹/L) 5
• Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL) 5
• Hemophagocytosis in bone marrow, spleen, or lymph nodes 5
• Low or absent NK cell activity 5
• Ferritin ≥500 μg/L 5
• Elevated soluble CD25 (IL-2 receptor) 5

When to Suspect HLH

If the patient has persistent fever and worsening cytopenias despite appropriate doxycycline treatment for confirmed ehrlichiosis, consider secondary HLH, as Ehrlichia chaffeensis is a documented trigger for this life-threatening hyperinflammatory syndrome 5

Special Considerations for Lyme Disease Diagnosis

Platelet Fraction Analysis

• The platelet fraction of blood concentrates Borrelia burgdorferi and may improve detection by PCR, culture, and Western blot compared to traditional serum or plasma samples 7
• Use citrate anticoagulant rather than EDTA when collecting blood for Borrelia culture or PCR to enhance pathogen viability 7

CD57 Lymphocyte Subset

• **Decreased CD57+ lymphocyte counts (<60 cells/μL) may indicate chronic Lyme disease** in patients with positive serology and prolonged symptoms (>3 months), though this is not part of standard diagnostic criteria 8

Clinical Context and Geographic Considerations

• Tick-borne rickettsial diseases should be considered endemic throughout the contiguous United States, not just traditionally high-risk areas 1, 2
• Do not exclude ehrlichiosis or anaplasmosis based on geography alone; approximately 5-15% of lone star ticks carry Ehrlichia chaffeensis, and 10-50% of Ixodes scapularis ticks carry Anaplasma phagocytophilum in endemic areas 2

Follow-Up Testing

• Repeat Lyme serology at 2-4 weeks if initial testing is negative but clinical suspicion remains high, as seroconversion may be delayed 1
• Repeat ehrlichiosis/anaplasmosis serology at 2-4 weeks to confirm diagnosis with rising titers 5, 6
• Monitor platelet counts every 24 hours until stable or improving 6
• Reassess CD57 counts after completing antibiotic therapy if chronic Lyme disease is diagnosed, as normalization correlates with clinical improvement 8