Ix and Mx of Eosinophilia (2016)
- Eosinophilia: >0.5 x10^9/L. ~4% of population
- Normal Eosinophil count higher in neonates, falls in elderly.
- No sex or ethnic variation.
- Hypereosinophilia syndrome (HES): >1.5 x10^9/L for 6 months with no underlying cause identified and signs of organ dysfunction present.
- HES Male: Female 9:1 due to FIP1L1-PDGFRA occurring exclusively in men
- Normal bone marrow eosinophil count 1-6%
- Production mainly controlled by IL-5, IL-3 and GM-CSF
- Normally found in lymphoid organs, GI mucosa and uterus.
- Eosinophilia drives migration to skin, heart and lungs where they cause organ dysfunction
- Clonal eosinophilia commonly due to tyrosine kinase gene fusions, usually involving platelet derived growth factor receptor (PDGFR) A and B, or fibroblast growth factor receptor 1 (FGFR1).
- History – allergy, skin, lymphadenopathy, GI, chest, detailed historical travel history
- Examination – skin, abdo, chest
- FBC + Film – true eosinophil count, morphology of eosinophils not helpful, parasites, evidence of other haematological disorders (blasts, dysplasia etc)
- U&E, LFT, LDH, CRP, ESR, Vit B12
- Further tests dependent on outcome of the above.
- If no reactive causes found
o Peripheral blood FISH for FIP1L1-PDGFRA (or PCR).
o Serum tryptase (systemic mastocytosis) à next test is KIT on bone marrow
o BMAT and cytogenetics
- Assess end organ damage
o CT, Echo, Troponin, Lung function tests
Reactive / Secondary Eosinophilia
Causes of Secondary / Reactive Eosinophilia
- Allergic – Asthma, dermatitis, eczema, hayfever
- Skin – Wells Syndrome
- Drugs – Antibiotics, anticonvulsants, herbs, diet supplements
- Infection – Parasites, fungi
- GI – Chronic pancreatitis, IBD, Coeliac, Eosinophilic oesophagitis
- Vasculitis – Polyarteritis nodosa, Churg-strauss (EGPA)
- Rheum – SLE, RA, Eosinophilic fasciitis (Shulman’s)
- Resp – Acute eosniphilic pneumonia (Loffler Syn), allergic bronchopulmonary aspergillosis, sarcoidosis.
- Cancer – Solid tumours, non-clonal eosinophilia in lymphomas and ALL, systemic mastcytosis
- Lymphocytic Variant Hypereosinophilia Syndrome (L-HES) – expansion of clonal T-lymphoid cells in peripheral blood with a secondary eosinophilia but without overt lymphoproliferative disease – Abnormal T cells on flow e.g. CD3-CD4+, CD3+CD4-CD8-
- Others – atheroembolic disease, GVHD, Gleich’s Syn (episodic angioeodema with eosinophilia), disorders of immune regulation (inc IgE syn, DOCK8 deficiency, PGM3 deficiency)
Notes on Secondary causes
- Wells Syndrome – an eosinophilic cellulitis with recurring granulomatous dermatitis. Sudden onset slate-blue plaques with ‘flame-figures’ histology and blood eosinophilia.
- Drugs – drug reaction with eosinophilia and systemic symptoms (DRESS) occurs 3-6 weeks after start of new drug, triad of skin eruption + fever + organ involvement
- EGPA / Churg-Strauss – pANCA +, rhinitis, hepatitis, diarrhoea, neuropathy, skin lesions
- Eosinophilic fasciitis (Shulman disease) – scleroderma like progressive skin thickening of limbs and trunk.
- Loffler Syn – transient pulmonary reaction 2-3 weeks after a parasitic infection, or 3-4 days after a new drug. Self-limiting.
- Non-clonal eosinophilia in cancer – present in 15% of hodgkins, up to 20% of NHL.
- Gleich’s Syn – monthly angio-oedema, self-resolves. Raised IgM, normal C1 esterase.
Infectious Causes of Secondary / Reactive Eosinophilia
- Strongyloidiasis – Tropics, Central and South America, Rural Europe, Africa, S and SE Asia - ELISA serology, fresh stool microscopy x3 – often asymptomatic
- Hookworm – tropical Asia, S America, Africa – Loffler Syndrome.
- Filariasis – Loa Loa, Wuchereria bancrofti – tropics – serology or day/night blood films – transient SC swelling (loa loa), lymphedema (Wuchereria)
- Ascariasis – tropics – ascending cholangitis – stool microscopy or USS liver
- Toxocariasis – visceral lava migrans – serology ELISA
- Trichinosis – undercooked pork – myositis, weakness, peri-orbital oedema – serology or muscle biopsy
- Schistosomiasis – freshwater swimming in tropics – S. mansoni portal hypertension, S. haematobium genitourinary complication.
- Invasive Aspergillosis and ABPA – chest symptoms – CT lungs, ABPA skin prick
- Coccidiodomycosis – deserts – pneumonia and erythema nodosum – serology, culture
- Fascioliasis – Somalia – watercress grown near sheep – biliary symptoms
Causes of Primary / Clonal Eosinophilia
- Myeloid / Lymphoid neoplasms with rearrangement of PDGFRA, PDGFRB, FGFR1 or with PCM1-JAK2, ETV6-JAK2, BCR-JAK2
- Chronic eosinophilic leukaemia, not otherwise specified (CEL-NOS) – includes cases with ETV6-ABL1, ETV6-FLT3 and other TK fusion genes. Blasts must be increased but <20%. Rare, aggressive disease with 20 month median survival.
- Atypical chronic myeloid leukaemia with eosinophilia (aCML-Eo)
- Chronic myelomonocytic leukaemia with eosinophilia (CMML-Eo)
- Acute myeloid leukaemia with eosinophilia (AML-Eo) – especially in t(8;21) or inv(16)
- T- and B-Acute lymphoblasrtic leukaemia (ALL)
- Systemic Mastocytosis
- Other myeloproliferative disorders in transformation
Idiopathic Eosinophilia / Idiopathic Hypereosinophilia Syndrome
- No detectable primary or secondary causes for eosinophilia.
- Diagnosis of exclusion
- No eosinophil count cut-off for emergency treatment in asymptomatic patients
- If organ damage, aim is to reduce count and tissue infiltration
o methylpred 1mg/kg/day or pred 0.5-1mg/kg.day
o 60-80% respond. Taper over 2-3 months.
o Allopurinol, PPI, bone protection
o Ivermectin if no time to test for strongyloides.
Chronic leukaemias with a specific molecular target
- FIP1L1-PDGFRA highly sensitive to low dose imatinib (100mg)
- PDGFRB or ETV6-ABL1 respond to imatinib 400mg
- ETV6-FLT3 respond to sunitinib or sorafenib
- PCM1-JAK2 or other JAK2 rearrangements respond to ruxolitinib
Chronic leukaemia without a specific molecular target
- Treat as for idiopathic HES
- Some respond to imatinib at 400mg, so give a trial for 4-6 weeks
- As for AML
- Imatinib 4-6 week trial
- Interferon-alpha – 1-5 million units/m2/day. Side effects are dose limiting
- Hydroxycarbamide as a steroid-sparing agent
- Mepolizumab / Reslizumab (Anti-IL5 monocolonal antibodies)
- HSCT – FGFR1 rearrangement and CEL-NOS have very poor prognosis and AML treatment followed by transplant may be justified.