What is the appropriate management for a patient with elevated Immunoglobulin E (IgE) and Immunoglobulin M (IgM) levels, and low eosinophil count, suggestive of a potential allergic or immune system disorder?

Elevated IgE and IgM with Low Eosinophils: Diagnostic Approach and Management

This pattern—elevated IgE and IgM with paradoxically low eosinophils—should prompt immediate evaluation for primary immunodeficiency disorders (PIDs), particularly those with immune dysregulation, as this combination is atypical for common allergic conditions and may indicate serious underlying pathology requiring urgent immunologic assessment. 1, 2

Why This Pattern Is Concerning

• Elevated IgE typically correlates with eosinophilia in allergic conditions, parasitic infections, and most atopic disorders, making the absence of eosinophilia a red flag that suggests an alternative pathophysiology 3, 4
• Low eosinophil counts in the setting of elevated IgE can indicate bone marrow suppression, consumption of eosinophils in tissues, or dysregulated immune signaling seen in certain PIDs 1, 2
• Elevated IgM alongside elevated IgE is uncommon in simple atopy and raises concern for immune dysregulation syndromes or combined immunodeficiency states 1, 2

Immediate Diagnostic Priorities

Rule Out Primary Immunodeficiency Disorders

• Obtain complete immunoglobulin panel including IgG, IgA, IgG subclasses, and repeat IgE and IgM levels to characterize the immunoglobulin pattern fully 3, 4
• Measure lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/56) to assess for combined immunodeficiency or lymphoproliferative disorders 1, 2
• Check inflammatory markers (CRP, ESR) and complete metabolic panel to assess for systemic inflammation or organ involvement 3
• Vitamin B12 levels should be obtained as B12 deficiency can affect eosinophil production 3

Assess for End-Organ Damage

• Screen for cardiac involvement with troponin, NT-proBNP, and ECG, as hypereosinophilic syndromes can cause myocardial damage even when peripheral eosinophils appear low due to tissue sequestration 5
• Obtain chest imaging to evaluate for pulmonary infiltrates or fibrosis that might indicate tissue eosinophilia despite low peripheral counts 5
• Consider tissue biopsy of any symptomatic organ system, as tissue eosinophilia can be present despite peripheral eosinopenia in certain conditions 5, 3

Specific PIDs to Consider

High-Priority Differential Diagnoses

• Hyper-IgE syndromes (STAT3 deficiency, DOCK8 deficiency) typically present with extremely elevated IgE (>2000 IU/mL), recurrent skin and lung infections, and eczema, though eosinophil counts can be variable 1, 2
• Wiskott-Aldrich syndrome can present with elevated IgE, thrombocytopenia, eczema, and recurrent infections, with variable eosinophil counts 1
• Omenn syndrome classically has severe eosinophilia but atypical presentations with dysregulated immune responses can occur 1
• Common variable immunodeficiency (CVID) can present with elevated IgE and IgM in some cases, particularly when complicated by autoimmune phenomena 1
• Autoimmune lymphoproliferative syndrome (ALPS) should be considered if lymphadenopathy, splenomegaly, or cytopenias are present 1

Clinical Red Flags Requiring Urgent Evaluation

• Recurrent sinopulmonary infections suggest antibody deficiency despite elevated immunoglobulin levels 6, 2
• Severe or treatment-resistant eczema in the context of elevated IgE warrants genetic testing for monogenic atopic disorders 6, 2
• Autoimmune manifestations (arthralgias, chronic fatigue, cytopenias) are more common in patients with immunoglobulin dysregulation 7
• Chronic diarrhea or failure to thrive may indicate enteropathy associated with immune dysregulation 1, 2

Alternative Explanations to Exclude

Medication Effects

• Review all medications for drugs that can suppress eosinophils (corticosteroids, immunosuppressants) while potentially elevating other immunoglobulins through immune dysregulation 4
• Immune checkpoint inhibitors can cause paradoxical immunoglobulin elevations with variable effects on eosinophils 3

Occult Malignancy

• Lymphoproliferative disorders can present with dysregulated immunoglobulin production and should be excluded with peripheral blood flow cytometry if lymphocytosis or atypical lymphocytes are present 3, 4

Tissue Eosinophilia Despite Peripheral Eosinopenia

• Eosinophilic esophagitis causes tissue eosinophilia but peripheral eosinophilia occurs in only 10-50% of adults, so normal or low peripheral counts do not exclude this diagnosis if dysphagia is present 8, 3
• Consider endoscopy with biopsies if gastrointestinal symptoms exist, as tissue diagnosis remains the gold standard 8

Management Algorithm

Step 1: Urgent Hematology/Immunology Referral

• Refer immediately to immunology for comprehensive evaluation including genetic testing if PID is suspected based on clinical context 5, 3
• Do not delay referral while awaiting test results if recurrent infections, severe eczema, or autoimmune features are present 6, 2

Step 2: Avoid Immunosuppression Until Diagnosis Established

• Do not initiate corticosteroids until infectious causes (particularly Strongyloides) are excluded and PID evaluation is complete, as steroids can precipitate hyperinfection syndrome or worsen underlying immunodeficiency 5, 9
• Hold off on empiric allergy treatment until the immunologic workup clarifies whether this represents true atopy versus immune dysregulation 8

Step 3: Monitor for Complications

• Serial complete blood counts to track eosinophil trends and identify development of cytopenias 5
• Repeat immunoglobulin levels in 4-6 weeks to assess stability versus progression 3
• Maintain high suspicion for infection given potential underlying immunodeficiency, and have low threshold for empiric antibiotics if fever develops 6, 2

Critical Pitfalls to Avoid

• Do not assume this is simple allergy based on elevated IgE alone—the absence of eosinophilia and presence of elevated IgM make common atopy unlikely 3, 4
• Do not rely on peripheral eosinophil counts to exclude tissue eosinophilic disorders, as tissue biopsy may be necessary 8, 5
• Do not overlook autoimmune screening as patients with immunoglobulin dysregulation have significantly higher rates of autoimmune disease (46% versus 15% in controls) 7
• Do not forget to exclude parasitic infections before any immunosuppression, particularly Strongyloides in anyone with travel history, as hyperinfection can be fatal 5, 9