Ix and Mx of Eosinophilia (2016)

 

Eosinophilia

-       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

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

-       Scabies

 

Clonal Eosinophilia

 

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

 

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

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

 

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.