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

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

  • 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.