Updated on: 09.06.2025

Eosinophilia

Introduction: 

• It is a condition in which absolute eosinophil count is more than 500/cmm 
• Hypereosinophilia (HE): AEC >1500/cmm on at least 2 occasions over an interval of at least 4 weeks
• Hypereosinophilic syndrome (HES): Elevation of peripheral blood eosinophils (>1500/cmm) for more than 4 weeks associated with end organ damage. (“syndrome” applies to organ damage that can be attributed to the eosinophilic infiltrate)
• Cause of HE or HES can be: 
  • Secondary/ Reactive
  • Primary/Clonal/Neoplastic
  • Idiopathic/ Unexplained.
• Definition of Idiopathic hypereosinophilia (Hypereosinophilia of uncertain significance): It is unexplained AEC >1500/cmm on at least 2 occasions over an interval of at least 4 weeks, but there is no end organ damage.
• Difference between CEL-NOS and Idiopathic HES/HE is- CEL-NOS is a clonal disorder, i.e. cytogenetic abnormality is present or they have abnormal bone marrow morphology.

Causes:

• Primary:
  • Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions ( PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ABL1, etc)
  • MPN with eosinophilia (eg, CML and JAK2 V617F+ MPN)
  • AML with inv(16) or t(16;16)/CBFB-MYH11
  • MDS with eosinophilia
  • MDS/MPN with eosinophilia
  • Aggressive systemic mastocytosis with eosinophilia
  • CEL-NOS
• Infections/ Infestations:
  • Helminthic (Most common cause worldwide)-Ascaris (Loffler’s syndrome), toxocariaris, Loa loa, filariasis (tropical pulmonary eosinophilia), river blindness, Hook worm, strongyloides stercoralis, trichinella spiralis, other intestinal worms, oncocerciasis, schistosomiasis, fasciola, ecchynococcosis, toxoplasma, Paragonimus, Clonorchis
  • Bacterial  
  • Mycobacterial 
  • Invasive fungal: coccidioides, histoplasma, cryptococcus, pneumocystis, aspergillosis
  • Rickettsial 
  • Viral: HIV, HSV, HTLV-2
• Allergic conditions 
  • Allergic rhinitis 
  • Atopic dermatitis 
  • Allergic gastroenteritis
  • Urticaria/ angioedema 
  • Asthma. 
  • Allergic bronchopulmonary aspergillosis (History of asthma, increased aspergillus specific IgE and IgG, IgE>1000ng/ml, wheal and flare skin reaction to aspergillus antigen, AEC- >1000/cmm) 
• Drugs 
  • Antibiotics: penicillin, cephalosporins 
  • NSAIDS 
  • Antipsychotics 
  • Phenytoin 
  • Diet supplements 
  • Herbal remedies 
  • Aspirin
  • GM-CSF therapy 
  • IL2 therapy for melanoma/RCC 
  • Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: Occurs 3-6  weeks after introduction of new drug, Triad of skin eruptions, fever and internal organ involvement (Lung, liver, kidney, LN or heart)
• Connective tissue diseases 
  • Hypersensitivity vasculitis 
  • Churg Strauss syndrome 
  • Serum sickness 
  • Eosinophilic fasciitis (Schulman's disease)- Scleroderma like syndrome of unknown cause, Painful swelling and induration of limbs and trunk, increased gamma globulins, increased ESR and increased AEC. 
  • Sjorgen syndrome 
  • Rheumatoid arthritis 
  • Polyarteritis nodosa 
  • Systemic lupus erythematosus
  • Inflammatory bowel disease
  • Celiac disease
  • Sarcoidosis
  • Systemic sclerosis
  • IgG4-related disease
• Neoplasms 
  • Internal malignancies- Ex: renal, lung, breast, vascular neoplasms, female genital tract cancers
  • Hematological malignancies- Hodgkin and Non-Hodgkin lymphoma, Langerhan's cell histiocytosis
• GI disorders 
  • Eosinophilic gastroenteritis 
  • Eosinophilic esophagitis 
  • Celiac disease 
  • Inflammatory bowel disease 
  • Allergic gastroenteritis 
  • Chronic pancreatitis 
• Respiratory disorders. 
  • Pulmonary eosinophilia (Loeffler syndrome)- Transient pulmonary reaction with reticulo-nodular shadowing on CXR associated  with peripheral blood eosinophilia, Low grade fever and cough for 7-10 days, Usually due to allergic reaction to parasites/drugs, Self limiting within 3-4 weeks of eliminating causal agent. 
  • Bronchiectasis, cystic fibrosis 
  • Hypersensitivity pneumonitis 
  • Eosinophilic pneumonia (At least 25% eosinophils in alveolar eaves) 
• Cardiac disorders:
  • Tropical endocardial fibrosis
  • Eosinophilic endomyocardial fibrosis or myocarditis
• Skin diseases. 
  • Atopic dermatitis 
  • Eczema
  • Scabies 
  • Myiasis 
  • Scarlet fever 
  • Bullous pemphigoid 
  • Eosinophilic cellulitis (Well syndrome)- Sudden onset of annular/ circinate erythematous edematous patches that rapidly evolve to morphea like slate blue plaques 
  • Recurring granulomatous dermatitis 
  • Dermatitis herpetiformis 
  • Herpes gestationalis 
  • Gleich syndrome (Variant of hypereosinophilic syndrome, recurrent episodes of angioedema, usually monthly intervals, sometimes associated with eosinophilic cellulitis, resolves spontaneously without therapy, corticosteroids decrease the severity of attack) 
• Inherited  disorders:
  • Wiskott aldrich syndrome 
  • Severe combined immunodeficiency (Swiss type/ X linked) 
  • Selective IgA deficiency with atopy 
  • Nezelof syndrome 
  • Hyper IgE syndrome (Job's syndrome) 
  • Familial hypereosinophilia: Autosomal dominant, beigins at birth, usually do not have eosinophilic activation, occurs due to dysregulation of IL-5 mRNA expression
  • DOCK 8 deficiency 
  • PGM3 deficiency 
• Miscellaneous:
  • Eosinophilia-Myalgia syndrome 
  • Toxic oil syndrome (Cooking oil contaminated with tryptophan) 
  • Cholesterol athero-embolic disease with catheterization procedure 
  • GVHD- Both acute and chronic 
  • Solid organ rejection
  • Adrenal insufficiency 
  • Benign eosinophilia (Increased eosinophils with no symptoms or organ damage) 
  • Angiolymphoid hyperplasia with eosinophilia (Kimura disease)
  • Lymphocytic variant of HES: Expansion of phenotypically aberant T lymphoid cells (eg, CD3+/CD4−/CD8− or CD3−/CD4+) with reactive eosinophilia, without overt lymphoproliferative disorder. Typically have cutaneous manifestations. Treated same as idiopathic HES.

Grading of eosinophilia: 

• Mild- Up to 1000/cmm 
• Moderate- 1000-5000/cmm 
• High- >5000/cmm 

Pathogenesis:

IL-5, IL-3, or granulocyte-macrophage colony-stimulating factor from activated T cells/ Mast cells/ stromal cells/ tumor cells

 or 

Tyrosine kinase gene fusions

↓

Increased proliferation of eosinophils which may subsequently infiltrate tissues

↓

Release of mediators such as eosinophil-derived cationic protein, major basic protein 1and 2, peroxidase, and neurotoxin

↓

Local inflammation, tissue remodeling, and sometimes tissue damage

↓

Tissue fibrosis and/or thrombosis with end-organ damage

Clinical features in hypereosinophilic syndrome:

• Skin (40%–70%): Pruritus, papule / plaques, angioedema, mucosal ulcers, vesciculo-bullous lesions
• Lungs (25%–40%): Pulmonary infiltrates, fibrosis, pleural effusion and pulmonary embolism
• Gastrointestinal tract (15%–35%): Diarrhoea, ascites, gastritis, colitis, pancreatitis, cholangitis, hepatitis, Budd chiary syndrome
• Heart (5%–20%) : Myocardial infarction, acute heart failure, thromboembolism, endomyocardial fibrosis, restrictive cardiomyopathy, Pericarditis, myocarditis, intramural thrombus formation, scarring of mitral / tricuspid valves leading to regurgitation
• Nervous system (5%–20%): Peripheral neuropathy, mononeuritis multiplex, paraparesis, cerebellar dysfunction, epilepsy, dementia, cerebrovascular accident, eosinophilic meningitis, encephalopathy, dementia
• Others- Microthrombi, vasculitis, retinal arteritis, digital necrosis, muscle pain, arthritis, arthralgia, Raynaud's phenomenon

Investigations: (Done based on initial evaluation and degree of clinical urgency) 

• Full blood count with peripheral smear- For blasts/ parasites 
• RFT 
• LFT 
• LDH 
• Uric acid 
• ESR and CRP- To rule out inflammatory/ reactive disease 
• Vitamin B12- Increased in case of myeloid disorders 
• Stool for ova and cyst 
• Serology for strongyloides, schistosomiasis, filariasis, toxocara 
• S. IgE levels 
• Quantitative immunoglobulin levels 
• Flow cytometry for T abd B subset analysis 
• BCR-ABL and PDGFR mutations 
• BM aspiration and biopsy  
  • Done if there is no identifiable cause and BCR-ABL and PDGFR mutations are negative.  
  • Same time perform cytogenetics and flow for CLPD 
• Chest X ray and spirometry 
• CT Chest and 2D Echo- for noting end organ damage. These should be done along with the tests done for cause of eosinophilia 
• S. Tryptase- For systemic mastocytosis 
• S. Cortisol 
• S. IL5 levels 
• GI biopsy 
• HIV and HTLV serology- In patients with suspected opportunistic infections 
• Flow cytometry for aberrant T-cell immunophenotype
• Investigations related suspected cause such as ANA, ANCA, bronchoscopy, imaging etc 
• NGS myeloid panel: Should be done if the karyotype is normal or of no diagnostic significance (eg, loss of Y chromosome in elders)

Compared to other hyper-eosinophilia patients with clonal/ neoplastic eosinophilia have:

• Constitutional symptoms, such as fever, weight loss, fatigue, cough, dyspnea etc
• Splenomegaly and/ or lymphadenopathy
• Peripheral blood: Presence of both mature and immature and/or dysplastic cells; anemia; abnormal platelet count (thrombocytopenia or thrombocytosis)
• Abnormal morphology in bone marrow: Increased blasts, dysplasia and bone marrow fibrosis
• Immunophenotypic aberrancy in the blast population
• Abnormal T cell population
• Patients are older
• High leucocyte count with high percentage of eosinophils and neutrophilia, monocytosis and/or basophilia
• Elevated S. Tryptase levels (>12 ng/mL)
• Increased Vitamin B12 levels (>1000 pg/mL)
• Eosinophilia that is refractory to steroids

Diagnostic algorithm: 

Idiopathic hypereosinophilic syndrome:  

• It has following characteristics 
  • Unexplained elevation of peripheral blood eosinophils (>1500/cmm) for more than 6 months 
  • No reactive causes of eosinophilia (Infections, allergy, autoimmunity, pulmonary conditions and neoplastic disorders)
  • No associated clonal myeloid neoplasms such as AML, MDS, MPN or systemic mastocytosis 
  • No cytokine producing immunophenotypically aberrant T cell population 
  • No increased myeloblast in the peripheral blood or bone marrow 
  • No evidence of clonality 
  • Associated end organ damage  

• Definition of Idiopathic hypereosinophilia/ Hypereosinophilia of unknown significance: It is same as above, but there is no end organ damage 
• If clonality is established (by cytogenetics/ PCR/ NGS for myeloid malignancies/High blast count- >2% in PB and >5% in BM), then such case are redefined as CEL-NOS. 

Treatment of eosinophilia in general: 

• Treatment of underlying cause in case of secondary eosinophilia 
• For primary/ clonal eosinophilia- Refer section on Chronic Eosinophilic Leukemia
• Steroids and hydroxyurea, to reduce eosinophil counts rapidly and to reduce end organ damage 
• In endemic areas use of broad spectrum antihelminthics is justified 
• Emergency treatment (For patients with severe eosinophilia with end organ damage/ life threatening eosinophilia- AEC>1lac/cmm/ Features of leukostasis) 
  • High dose corticosteroids- Methyl prednisolone- 1mg/kg/day/ Oral prednisolone- 0.5mg- 1mg/kg/day for 2 weeks, then taper over 2-3 months to lowest possible dose to maintain response 
  • Give concomitant Ivermectin, if there is suspicion of strongyloides (200microgm/kg/day for 2 days) 
• Treatment of idiopathic hypereosinophilic syndrome 
  • 1st line- Steroids (Prednisolone 0.5-1mg/kg/day) for 2 weeks, then slowly taper over 2-3 months to a lowest possible dose to maintain a response. Ivermectin cover (200microgm/kg- OD for 2 days) has to be given initially 
  • 2nd line (If there is inadequate response to steroids/ if there is need for prolonged steroid therapy/ intolerance to steroids) Short trial (4-6 weeks of following may be tried 
    • Imatinib- 400mg- OD- May be useful in patients without PDGFR mutation 
    • Interferon alpha- 1-5 million units/m2/day for initial few doses, then lower the doses as maintenance 
    • Azathioprine- 1-3mg/kg/day- Adjust the doses based on the response 
    • Ciclosporine- 150-300mg/day 
    • Hydroxyurea- 500-3000mg/day 
    • Cyclophosphamide
    • Targeted therapies:
      • Mepolizumab and Reslizumab- Anti-IL5 antibody
      • Benralizumab- Binds to alfa chain of IL-5 receptor and induces eosinophil death via antibody dependent cell cytotoxicity (throgh NK Cell)
      • Lirentelimab- Antibody to Singlec8 that depletes eosinophils and inhibits mast cell activation
      • Dupilumab- Monoclonal antibody to IL4 receptor alfa. Approved for treatment of eosinophilic esophagitis
      • Dexpramipexole: Causes maturation arrest and eosinophilic depletion through an unknown mechanism
  • 3rd line (If not responding to any of the 2nd line agents) 
    • Alemtuzumab 
    • Hematopoietic stem cell transplantation 

Basophilia

• It is a condition in which absolute basophil count is more than 100/cmm 
• Causes 
  • Allergy or inflammation (Associated with increased IgE)-  
    • Ulcerative colitis 
    • Drug, food, inhalant hypersensitivity 
    • Erythroderma, urticaria 
    • Juvenile rheumatoid arthritis. 
  • Endocrinopathy 
    • Diabetes mellitus 
    • Estrogen administration 
    • Hypothyroidism 
  • Infections 
    • Chicken pox 
    • Influenza 
    • Tuberculosis 
  • Iron deficiency 
  • Exposure to ionizing radiations 
  • Neoplasia 
    • MPN- CML, PV, PMF, ET 
    • AML with  t (9:22)  and t(3:6) or 12p abnormalities 
    • AML with basophilic maturation 
    • Carcinoma