Guideline for the investigation and management of eosinophilia

• DOI: 10.1111/bjh.14488
• Publication Date: 2017-01-23T12:17:02Z
• Authors: Nauman M. Butt; Jonathan Lambert; Sahra Ali; Philip A. Beer; Nicholas C. P. Cross; Andrew Duncombe; Joanne Ewing; Claire N. Harrison; Steven Knapper; Donal McLornan; Adam J. Mead; Deepti Radia; Barbara J. Bain
• Keywords: Guideline; Hypereosinophilic Syndrome; Hypereosinophilia; Hematology

The guideline group was selected to be representative of UK-based medical experts with an interest in myeloproliferative neoplasms and eosinophilia. PubMed EMBASE were searched systematically for publications English until August 2015 using the key words eosinophilia, hypereosinophilia, eosinophilic leukaemia HES. writing produced draft guideline, which subsequently revised by consensus members General Haematology Haemato-oncology Task Forces British Committee Standards (BCSH). then reviewed a sounding board UK haematologists representatives from Nordic MPN Study Group, BCSH Society (BSH) Committee, comments incorporated where appropriate. ‘GRADE’ system used quote levels grades evidence, details can found Table 1. objective this is provide healthcare professionals clear guidance on investigation management There no previous topic. purpose practical approach history should include: Assessment possible eosinophil-associated end-organ damage Emergency treatment Treatment clonal eosinophilia lymphocytic variant hypereosinophilic syndrome idiopathic Role haemopoietic stem cell transplantation (HSCT) Eosinophilia defined as elevation eosinophil count above observed healthy subjects, usually taken 0·5 × 109/l. Eosinophil counts are higher neonates than adults values gradually fall elderly. sex or ethnic variation count. Definitions hypereosinophilia (HE) (HES) based proposal Chusid et al (1975) 1·5 109/l greater persisting at least 6 months, underlying cause associated signs organ involvement dysfunction. This criterion accepted World Health Organization (WHO) classification chronic (CEL), not otherwise specified (CEL, NOS) (Bain al, 2008, pp. 51–53). However withheld patients less months duration who have evidence (see treatment). normal bone marrow contains between 1% 6% eosinophils these produce peripheral blood 0·05–0·5 (Valent 2012). production tightly controlled network transcription factors (McNagny & Graf, 2002) driven various cytokines, principally interleukin (IL) 5, IL3 granulocyte-macrophage colony-stimulating factor (GM-CSF) activated T lymphocytes, stromal cells mast cells, triggering differentiation activation (Ackerman Bochner, 2007). Such cytokines also main drivers reactive contrast tyrosine kinase gene fusions common, typically involving genes coding platelet-derived growth receptor alpha (PDGFRA), beta (PDGFRB) fibroblast 1 (FGFR1) (Gotlib 2006). Under conditions, may lymphoid organs mucosa gastrointestinal tract uterus but very rarely other tissues. However, prolonged marked migration into non-native tissues, such skin, heart lung, they through induction thrombosis fibrosis (Gleich, 2000). Primary disorders rare probably under-diagnosed conditions. A large population study general practice setting Copenhagen demonstrated incidence (defined 109/l) 4% (Andersen 2015). causes numerous conventionally divided three categories – secondary (reactive), primary indicated 2. These discussed below. HES predominantly affects males, estimated male-to-female ratio ranging up 9:1 (Weller Bubley, 1994). largely explained fact that FIP1L1-PDGFRA fusion occurs almost exclusively males. In case series 188 subjects HES, once confirmed FIP1L1-PDGFRA-positive removed cohort, difference prevalence statistically significant (Ogbogu 2009). form majority cases Allergic disorders, atopic dermatitis, asthma seasonal allergic (rhinitis/hayfever), result cytokine-driven non-clonal mild (less degree tissue infiltration generally correlating severity disease (Horn 1975). resolves control condition. Wells (eosinophilic cellulitis) recurring granulomatous dermatitis (Wells, 1971) characterised (i) sudden onset annular circinate erythematous-oedematous patches rapidly evolve morphoea-like slate-blue plaques, (ii) histological appearance characterized presence ‘flame figures’ (iii) inconstant Similar appearances seen dermatological conditions often discriminated clinically. variants been described (El-Khalawany 2013) well associations affecting including connective (Yin Xie, Drug hypersensitivity always considered unexplained list agents extensive includes dietary supplements herbal remedies (Klion, clinical manifestations drug-induced range asymptomatic life-threatening Rarely, drug reaction systemic symptoms (DRESS syndrome) 3–6 weeks after introduction new drug. triad skin eruption, fever internal (lung, liver, kidneys, lymph nodes heart) (Dong 2014; Sultan Drug-induced vasculitis reported, manifesting purpura, arthralgia myalgia kidney lung (Roujeau 2014). detailed review infectious has recently published (O'Connell Nutman, Important infective their diagnostic tests outlined 3. Infection Hospital Tropical Diseases recommendations tropical travel (Checkley 2010). Travel tropics: South, Southeastern Central America, rural areas Europe, sub-Saharan Africa, South Asia, Southeast Asia Skin: localized, pruritic, erythematous papular rash site penetration; migrating pruritic (cutaneous larva migrans); generalised GI: abdominal pain, weight loss, diarrhoea, vomiting Lung: cough, wheeze, dyspnoea, haemoptysis Usually asymptomatic. raised absolute only feature (but immunosuppression make falsely normal) Serology (ELISA): sensitive specific, false negatives immunocompromised Fresh stool microscopy: relatively insensitive parasitic larvae present intermittently cases, microscopy sputum bronchoalveolar lavage fluid useful Check serology all travellers suggestive features arriving endemic region. before starting corticosteroids living If positive, treat strongyloidiasis steroids minimise risk hyperinfection Hookworm (Ancylostoma duodenale Necator americanus) area (mostly subtropical Latin America) Often Symptoms heavily infected migrants; Loffler's pneumonia occur vomiting, iron-deficiency, malnutrition Filariasis (Loa loa, Wuchereria bancrofti, Mansonella perstans, Brugia malayi, onchocerca spp.) (tropics) Severe pruritus /or corneal precipitates (onchocerca Transient subcutaneous swellings loa) Lymphoedema (W. bancrofti B. malayi) Filaria (ELISA) Day/night smears microfilariae timing depends species Skin snips slit lamp examination (Onchocerca volvulus) Ascariasis (Ascaris lumbricoides) (tropics), more common children ascending cholangitis, obstructive jaundice, bile duct perforation, bowel obstruction (all rare) eggs Ultrasonography demonstrate hepatobiliary pancreatic ascariasis Toxocariasis (Toxocara canis or, commonly, Toxocara cati) Contact domestic dogs cats asymptomatic; anorexia Rarely visceral migrans (hepatitis pneumonitis), ocular, neurological cardiac Trichinosis (Trichinella Ingestion undercooked pork (or meats) several days May asymptomatic, fever, headache, diarrhoea. Musculoskeletal (due invasion muscle parasite): myositis, weakness, swelling peri-orbital oedema. affect respiratory muscles rarely, lungs CNS (ELISA, latex agglutination) negative first 3–4 infection Occasionally Western blot biopsy needed Schistosomiasis (Schistosoma (typically America east Asia), freshwater swimming Acute symptoms: localised (‘swimmer's itch’), myalgia, dry pain S. mansoni: hepatosplenomegaly portal hypertension haematobium: genitourinary ‒ haematuria, squamous carcinoma, uropathy due ectopic brain spinal cord manifestation Urine fresh (low sensitivity low-level early infection) Abdominal imaging (ultrasound CT) Invasive aspergillosis bronchopulmonary (Aspergillus Background cystic expectoration brown mucus plugs, haemoptysis, lobar consolidation Wide invasive aspergillosis, especially CT lungs: bronchiectasis infiltrates ABPA; classically cavitating nodules surrounded ground-glass ABPA: prick test reactivity aspergillus antigens serum antibodies spp, total IgE aspergillosis: fungal culture samples; stained Grocott's methenamine silver Coccidioidomycosis (Coccidioides desert areas, northern central pneumonia, followed arthralgia, erythema nodosum Culture specimens, biopsy, +/− PCR Fascioliasis (Fasciola hepatica) follows ingestion watercress grown sheep-raising transmitted via water lettuce, mint khat (common some Somali communities) right upper quadrant jaundice (may initially, extreme eosinophilia) ultrasound show liver tracks abscesses Scabies (Sarcoptes scabiei) Widespread, intensely rash, worse night Erythematous papules Other family affected without 4 highlights need differential diagnosis. (1) oesophagitis (2) gastritis (3) colitis Polyarteritis nodosa (PAN) results inflammation injury medium-sized small arteries, leading ischaemia haemorrhage variety tissues organs, though kidneys spared. Renal sparing antineutrophil cytoplasmic (ANCA) differentiating PAN necrotizing vasculitides (Hernandez-Rodriguez occasionally but, when present, granulomatosis polyangiitis must (Watts Eosinophilic (EGPA/Churg-Strauss syndrome): EGPA clinicopathological depending involved: rhinitis, acute hepatitis, diarrhoea (mesenteric ischaemia), restrictive cardiomyopathy, neuropathy, lesions and, renal disease. ANCA support diagnosis mostly perinuclear (p-ANCA) against myeloperoxidase (MPO); however positive 50% (Sablé-Fourtassou 2005; Sinico 2005). biopsy. Systemic lupus erythematosus (SLE): uncommonly individual reports there systematic studies SLE does one criteria condition (Petri fasciitis (Shulman disease): scleroderma-like unknown cause, thought immune-mediated resultant painful progressive induration thickening skin/soft limbs trunk. Laboratory findings those hypergammaglobulinaemia elevated erythrocyte sedimentation rate (ESR). universally recent (Pinal-Fernandez 2014), formed four minor association aplastic anaemia (de Masson 2013). Rheumatoid arthritis (RA): prospective French showed approximately 3% RA transient (Guellec Although differ Danish study, same manner 2015), did appear predict poorer response disease-modifying antirheumatic use 3 years smaller Argentinian 7% amongst patients, (Chiardola 2008). number pneumonias. extensively (Cottin, 2016). Their characteristic radiological demonstration alveolar 25% broncho-alveolar lavage. Peripheral Löffler disease, sarcoidosis. disease: pulmonary reticulonodular shadowing chest radiology 1932 (Loffler, 1932). Patients low grade cough 7 10 days, alveoli Infectious disease) medications Drug-induced). lesions. 2 following exposure parasites medication. self-limiting subsiding within eliminating causal agent. aspergillosis. caused Aspergillus fumigatus uncontrolled recurrent progress (Agarwal Diagnostic include fibrosis, aspergillus-specific immunoglobulin (Ig) E IgG, (1000 ng/ml >417 iu/ml), wheal-and-flare antigen 1·0 Sarcoidosis: sarcoidosis angiotensin converting enzyme level demonstrating non-caseating granulomas suggests Solid tumours: non-haematological reported 0·5–7% (Montgomery advanced metastatic careful evaluation carried out exclude occult malignancy Reactive broad spectrum B- T-cell lymphoproliferative disorders. Hodgkin lymphoma 15% (Vaughan Hudson 1987) non-Hodgkin ranges 2% 20% B-cell lymphomas. lymphoblastic leukaemia/lymphoma (Grimaldi Meeker, 1989). B-lineage (ALL) t(5;14)(q31.1;q32.1), it dysregulation proximity IGH locus. When part neoplastic clone rather falls haematological Lymphocytic (L-HES) expansion demonstrably phenotypically aberrant T-lymphoid secondary, (Simon 1999), overt abnormal populations 17–27% 1999; Ogbogu current rests flow cytometry, phenotypes CD3− CD4+, CD3+ CD4− CD8− CD4+ CD7− (Roufosse, Some L-HES harbour rearrangement alone insufficient absence Clinical cutaneous 1999) severe manifestations, involvement. Atheroembolic cholesterol atheroembolic develops consequence microembolisation rupture atheromatous aortic plaques arterial catheterisation procedures, vascular surgery anticoagulant thrombolytic therapy. phase illness (Kasinath Lewis, 1987; Scolari 2007), increased IL-5 surface emboli (Cogan 1995). organ. both GVHD allogeneic haematopoietic (Jacobsohn 2004; Imahashi 2010; Ahmad 2011) although mechanisms unclear. Conflicting data exist regarding prognostic significance (Imahashi 2011). 1984 (Gleich 1984) episodic angio-oedema monthly intervals spontaneously Cyclic eosinophil, neutrophil lymphocyte (Khoury It IgM C1 esterase normal. previously believed lead end report progressed endomyocardial (Wright Corticosteroids reduce attacks. Hypereosinophilia immune deficiency dysregulation. paediatric age features, infections predisposition malignancy. description beyond scope article (Williams autosomal dominant hyper-IgE syndrome, DOCK8 PGM3 similar particularly notable markedly levels. accompanied clone, thus primary. listed Clonal suspected isolated possibly representing CEL, consistent myelomonocytic atypical myeloid JAK2V617, KITD816V PDGFRA, PDGFRB FGFR1 68–73), PCM1-JAK2 Ahmad, 2014) BCR-JAK2 ETV6-JAK2 ETV6-ABL1 (Nand 2009) ETV6-FLT3 (Walz BCR-ABL1-positive do disproportionate clonal; predominant time acceleration blast transformation. (AML) t(8;21)(q22;q22.1) inv(16)(p13.1q22) prominent (AML-Eo). Apparent AML-Eo represent transformation neoplasm (MPN) FGFR1. ALL either arising pluripotent lymphoid-myeloid clonal. T-ALL/T PDGFRA rearrangements ETV6-FLT3; (Chmielecki 2012; Ondrejka unspecified (Metzgeroth MPNs rearrangement. B-ALL/B (Trempat 2003). mixed phenotype monoblastic/precursor-B (Yamamoto 2006) context. Cases suffer B mastocytosis postulated cytokine driven, combination two. By definition, NOS BCR-ABL1-negative p 51-53). PCM1-JAK2, excluded. distinction AML-Eo, t(8;21) inv(16) absent. increase neutrophils monocytes occasionally, basophils. For recognised leukaemic nature cytogenetic clonality. Cytogenetic abnormalities included trisomy 8 i(17q). aggressive disorder median survival 20 high 2011; Helbig Idiopathic HE diagnoses exclusion appropriately assessed history, physical thorough any being found. Both (Chusid 1975) with, damage. Organ systems involved heart, lungs, nervous tract. Thromboembolic complications common. likely consequent unrecognised cause. Others sometimes follow-up occurs. centred investigating assessing investigations performed parallel. process begins assessment asthma, eczema, urticaria hay fever. rashes lymphadenopathy sought. Cardiorespiratory evaluated. Constitutional noted drenching sweats, alcohol-induced pain. travel, taken; even remote past relevant. taken. performed. Initially, full film examined. verify because hypogranular counted accurately automated counters. arbitrary 51-53) molecular analysis permits certain entities diagnosed lower count). indicate alternative morphological neoplasm, neutrophilia left shift, monocytosis, basophilia, dysplastic circulating cells. cytological helpful given striking cytologically fairly Routine renal, profile, lactate dehydrogenase ESR and/or C-reactive protein. latter excluding inflammatory Vitamin B12 assayed point disorder. Further testing dependent initial investigations, urgency. Suggested 5. moderate 109/l, further indicated. persistent (at 109/l), damage, additional Secondary (reactive) excluded stage. obvious considered. suggested algorithm shown Fig non-urgent situation, prudent fluorescence situ hybridisation (FISH) nested reverse polymerase chain (RT-PCR). Serum tryptase estimation if CEL mastocytosis. Otherwise, aspirate, trephine