Ix and Mx of Eosinophilia (bsh 2016)
intro
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
Biology
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).
Clinical Assessment
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
Peripheral blood FISH for FIP1L1-PDGFRA (or PCR).
Serum tryptase (systemic mastocytosis) à next test is KIT on bone marrow
BMAT and cytogenetics
Assess end organ damage
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
Scabies
Clonal Eosinophilia
Causes of Primary / Clonal Eosinophilia
Chronic Eosinophilic Leukaemia (WHO-HAEM5)
Multi-system disorder of sustained (>4 weeks) clonal proliferation of morphologically abnormal eosinophils
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) (WHO-HAEM5)
E.g. rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2, FLT3
E.g. fusions of PCM1-JAK2, ETV6-JAK2, BCR-JAK2
Idiopathic Eosinophilia / Idiopathic Hypereosinophilia Syndrome
No detectable primary or secondary causes for eosinophilia.
Diagnosis of exclusion
Treatment
Emergency Treatment
No eosinophil count cut-off for emergency treatment in asymptomatic patients
If organ damage, aim is to reduce count and tissue infiltration
Steroids
Methylpred 1mg/kg/day or pred 0.5-1mg/kg.day
60-80% respond. Taper over 2-3 months.
Allopurinol, PPI, bone protection
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
AML-Eo
As for AML
Idiopathic HES
Steroids
Imatinib 4-6 week trial
Interferon-alpha – 1-5 million units/m2/day. Side effects are dose limiting
Ciclosporin
Azathioprine
Hydroxycarbamide as a steroid-sparing agent
Mepolizumab / Reslizumab (Anti-IL5 monocolonal antibodies)
Alemtuzumab
HSCT – FGFR1 rearrangement and CEL-NOS have very poor prognosis and AML treatment followed by transplant may be justified.