Eosinophilia

Introduction: 

• It is a condition in which absolute eosinophil count is more than 500/cmm 

Causes 

• Infections 
  • Helminthic (Most common cause word wide)-Ascaris (Loffler’s syndrome), toxocariaris, Loa loa, filariasis (tropical pulmonary eosinophilia), river blindness, Hook worm, strongyloidesstercoralis, trichinellaspiralis, other intestinal worms, oncocerciasis, schistosomiasis, fasciola, ecchynococcosis. 
  • Bacterial 
  • Mycobacterial 
  • Invasive fungal 
  • Rickettsial 
  • Viral 
• Allergic conditions 
  • Allergic rhinitis 
  • Atopic dermatitis 
  • Urticaria/ angioedema 
  • Asthma. 
  • Allergic bronchopulmonaryaspergillosis (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 
• 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 
  • Polyarteritisnodosa 
  • SLE 
  • Rheumatoid arthritis 
• Neoplasms 
  • Internal malignancies- Ovarian carcinoma, mucin secreting carcinomas 
  • Hematological malignancies- CML, Chronic eosinophilic leukemia, systemic mastocytosis, CEL with PDGFRA/PDGFRB mutation, Hypereosinophilic syndrome-NOS, angioimmunoblasticlymphadenopathy, AML with chromosome 16 abnormalities, AML with t (8:21), Lymphoma (mostly with HD), Langerhan's cell histiocytosis, ALL with t (5:14), CMML with eosinophilia, Atypical CML with eosinophilia, CML with accelerated phase 
• 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) 
• Skin diseases. 
  • Atopic dermatitis 
  • 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 
• Miscellaneous 
  • Wiskottaldrich syndrome 
  • Severe combined immunodeficiency (Swiss type/ X linked) 
  • Selective IgA deficiency with atopy 
  • Nezelof syndrome 
  • GM-CSF therapy 
  • IL2 therapy for melanoma/RCC 
  • 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 
  • Eosinophilia-Myalgia syndrome 
  • Toxic oil syndrome (Cooking oil contaminated with tryptophan) 
  • Cholesterol athero-embolic disease with catheterization procedure 
  • GVHD- Both acute and chronic 
  • Adrenal insufficiency 
  • Sarcoidosis 
  • 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) 
  • Benign eosinophilia (Increased eosinophils with no symptoms or organ damage) 
  • Lymphocytic variant of HES (Expansion of phenotypically aberant T lymphoid cells with reactive eosinophilia, without overt lymphoproliferative disorder. Typically have cutaneous manifestations. Treated same as idiopathic HES) 
  • 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) 

Grading of eosinophilia: 

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

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 
• Investigations related suspected cause such as ANA, ANCA, bronchoscopy, imaging etc 

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 
  • 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 
• 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) 
  • 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