Idiopathic hypereosinophilic syndrome with

Case report

Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases Faisal Inayat,1 Stacey S O’Neill,2 Fahad Zafar,3 Sindhuja Marupudi,2 Izzah Vasim2 1

Allama Iqbal Medical College, Lahore, Pakistan 2 Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA 3 King Edward Medical University, Lahore, Pakistan Correspondence to Dr Faisal Inayat, faisalinayat@hotmail.com Accepted 10 November 2018

Summary Although idiopathic hypereosinophilic syndrome (HES) is uncommon, we studied the clinical characteristics of this disorder in patients with cutaneous involvement. We chronicle the case of a patient with diffuse skin rash due to idiopathic HES from our clinical experience. Furthermore, a systematic literature search of the medical databases PubMed and Google Scholar was conducted. A total of 32 cases fulfilled the inclusion criteria. The data on patients’ characteristics, epidemiology, clinical features, diagnosis, treatment and outcome were collected and analysed. This review illustrates that physicians should maintain a high index of clinical suspicion for idiopathic HES in patients presenting with dermatological lesions and hypereosinophilia, without an obvious cause. Randomised clinical trials are warranted to outline a generalised and efficient therapeutic approach in these patients. Additionally, this paper highlights the need for population-based studies to delineate the magnitude and scope of this association.

Background

Hypereosinophilic syndrome (HES) was first described in 1968 by Hardy and Anderson.1 It is an uncommon, multisystem, heterogeneous group of disorders with significant morbidity and mortality.2 3 The Surveillance, Epidemiology, and End Results data show that the estimated morbidity is between 0.036/100 000 and 6.3/100 000 whereas the mortality is about 9.3%.4 This disorder has

© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Inayat F, O’Neill SS, Zafar F, et al. BMJ Case Rep 2018;11:e227137. doi:10.1136/bcr-2018227137

Figure 2 Diffuse, papular rash involving the back. been categorised into several subtypes, including lymphocytic variant, myeloid, eosinophilic granulomatosis with polyangiitis overlap, single-organ, and idiopathic disease.4 Idiopathic HES is characterised by peripheral blood eosinophilia (>1.5 × 109/L) for at least 6 months and associated organ damage, without any identifiable underlying aetiology. Based on the limited data, this variant has no clear gender predominance with an estimated male to female sex ratio of 1:1.4 Diagnosis is established by exclusion of known causes of hypereosinophilia such as infections, parasites, allergy, vasculitis, malignancy and haematological disorders. Multiorgan involvement is frequently noted in these patients.4 In this study, we present the case of a patient who developed skin rash without any clear aetiology. He was eventually diagnosed with idiopathic HES on the basis of consistent clinical features, laboratory findings and exclusion of probable aetiologies. Furthermore, we review the pertinent medical literature for idiopathic HES with cutaneous involvement and summarise the data retrieved from the previously reported relevant cases. This review outlines our current understanding of the epidemiology of and risk factors for idiopathic HES-related cutaneous manifestations, the pathophysiology of this disorder and the currently available approaches to diagnosis and management.

Case presentation Figure 1 Multiple erythematous plaques associated with fine scaling and crusting present on bilateral lower extremities with several erythematous papules coalescing to form plaques.

A 57-year-old Caucasian man with a formidable medical history of chronic obstructive pulmonary disease, irritable bowel syndrome, Ludwig’s angina, trigeminal neuralgia and gastro-oesophageal reflux disease presented to our medical centre with diffuse

Inayat F, et al. BMJ Case Rep 2018;11:e227137. doi:10.1136/bcr-2018-227137

1

BMJ Case Rep: first published as 10.1136/bcr-2018-227137 on 3 December 2018. Downloaded from http://casereports.bmj.com/ on 4 December 2018 by Steve Newton. Protected by copyright.

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Figure 3 Cutaneous lesions consistent with erythematous plaques and papules on the left arm and forearm. skin rash, shortness of breath and facial swelling for 5 months. Multiple pruritic, erythematous papules and plaques of varying sizes were present predominantly over the left lower extremity, also involving the back and left upper extremity (figures 1–3). The skin lesions had a waxing and waning course for the past several months despite the use of oral corticosteroids.

Investigations

The patient underwent an extensive diagnostic workup. The details of his laboratory evaluations are provided in table 1. Initial laboratory studies revealed a prominent eosinophilia of 3.5×109/L (normal, 0.05–0.5×109/L). An extensive inpatient diagnostic workup was performed following the directions of a multidisciplinary consult team. Rheumatological and immunological studies showed positive titre of antinuclear antibodies and elevated C-reactive protein. However, testing for anti-ds DNA, anti-Smith antibodies, anti-Sjögren’s-syndrome-related antigen A (anti-SSA) autoantibodies, anti-ACE 1 antibody, antineutrophil cytoplasmic antibodies, complement C3 and C4, C1 esterase inhibitor, and anti-Jo-1 antibodies were all negative. IgG, IgE, IgA and interleukin (IL)-5 were within normal limits. The studies for rapid plasma reagin, HIV, strongyloides, human herpesvirus 1 and 2, cytomegalovirus, Epstein–Barr virus, Lyme

Table 1 Initial laboratory investigations of the patient with respective reference ranges Laboratory parameter Specimen

Patient result

Reference range

White cell count

13.3×109/L

4.8–10.8×109/L

Red cell count

Serum Serum

9

4.77×10 /L

4.70–6.10×109/L

Haemoglobin

Serum

14.8

14–18 g/dL

Haematocrit

Serum

44.7

42.0%–52.0% 9

9

Platelets

Serum

2.44×10 /L

1.5–4.5×10 /L

Total protein

Serum

6.7

6.0–8.3 g/dL

Albumin

Serum

3.5

3.5–5.0 g/dL

Total bilirubin

Serum

0.5

0.1–1.2 g/L

AST

Serum

19

5–40 IU/L

ALT

Serum

15

5–50 IU/L

ALP

Serum

81

25–125 IU/L

Blood urea nitrogen

Serum

10

7–20 mg/dL

Creatinine

Serum

1.04

0.4–1.2 mg/dL

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase.

2

disease, streptococcal pharyngitis, blood culture, acid-fast and fungal cultures, procalcitonin test, Chlamydia, Giardia, viral hepatitis panel, Histoplasma and coccidiomycoses were all unremarkable. Similarly, thyroid-stimulating hormone, vitamin B12, folic acid, zinc and niacin were within respective normal ranges. Salivary gland biopsy was inconclusive. Skin biopsy showed acute spongiodermatitis with a few eosinophils. Peripheral smear revealed normal red-cell morphology with marked eosniphilia and no blast cells. Subsequently, an uneventful bone marrow biopsy (BMB) was performed. Histopathological analysis of the biopsy specimen showed significant increase in eosinophils with no signs of malignancy (figure 4). On a higher magnification power, marked eosinophilia was evident with eosinophils showing large acidophilic cytoplasmic granules (figure 5). The specimen demonstrated normal cytogenetics. The FIP1L1/PDGFRA, BCR/ABL fusion product or T-cell receptor gene rearrangement were not detected. Flow cytometry on bone marrow was also negative. In order to assess the eosinophilia-mediated end-organ damage, CT chest was performed that showed early-onset ground-glass opacities with no fibrosis (figure 6). Her urine routine examination and microscopy were negative for abnormalities. A bronchoalveolar lavage analysis via bronchosocpy showed 11% eosinophils. Echocardiography was negative for any endomyocardial thickening. Otolaryngoscope ruled out upper airway oedema. Subsequently, the eosinophil count trended upward to 6.7×109/L. Additionally, the patient was not on any medications that commonly demonstrate a propensity to cause drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.

Treatment

Due to the consistent clinical presentation and negative diagnostic workup for prominent eosinophilia, the patient was diagnosed with idiopathic HES. He was educated about the disease and was initiated on high-dose (1 mg/kg/day) intravenous corticosteroid therapy.

Outcome and follow-up

He showed clinical improvement of his condition with steroids. Considering the long course of symptoms, he was discharged on high-dose oral therapy with 60 mg/day prednisone. At the 1-month follow-up, he reported good response with diminution of symptoms. Over the next 4 months, the dose was tapered down to 30 mg/day. The eventual plan was to taper it down by 5 mg every week to zero. However, the skin rash remained persistent due to which the dose was only reduced to 7.5 mg/ day. His cutaneous as well as systemic symptoms remained stable thereafter. On subsequent follow-ups, he neither reported any inadvertent events nor experienced recurrence of the disease. The patient continues to do well to date.

Discussion

Idiopathic HES is a potentially severe and debilitating multisystem disorder associated with considerable morbidity. Cardiac, nervous system, respiratory tract and cutaneous involvements have frequently been reported while gastrointestinal disease is relatively less common.1 2 Although the exact pathogenesis of HES is unknown, the disease process has been theorised to be linked with abnormal IL-5 levels. CD3−/CD4+T-helper 2 cells with abnormal immunophenotype produce various ILs, including IL-5, which maintain an increased population of eosinophils leading to HES. IL-5, which is also produced by eosinophils, has a selective role in eosinophil maturation, Inayat F, et al. BMJ Case Rep 2018;11:e227137. doi:10.1136/bcr-2018-227137


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Figure 4 Photomicrograph of bone marrow biopsy demonstrating abundant eosinophils with no signs of malignancy or other abnormalities. (H&E; 20×). differentiation, mobilisation, activation and survival.3 Since IL-5 appears to contribute to the pathogenesis of some phenotypes of HES, its inhibition is a logical therapeutic target for this disease. However, it was an interesting aspect of the present case that IL-5 levels were within normal limits. A few gene aberrations can also contribute to the pathophysiology of this disorder. The patients in the paediatric age group usually have trisomy 8 or ABL oncogene translocation while adults have FIP1L1/PDGFRA fusion due to interstitial deletions on chromosome 4.4 Several intracellular chemicals, including eosinophil peroxidase, major basic proteins, granule proteins, neurotoxins and cationic proteins, are stored in eosinophils in the form of granules that can cause tissue damage.4 The eosinophils in these patients show overexpression of CD25 on their surface as well as increased production of IL-2, culminating in the degranulation of these chemicals (systemic mastocytosis) leading to the cutaneous and other symptoms.4 We systematically searched the published medical literature in order to retrieve the available data for idiopathic HES with cutaneous involvement. The articles were collected as of September 2018 using the medical databases, PubMed (National Library of Medicine, Bethesda, Maryland, USA) and Google Scholar. Different MeSH (Medical Subject Headings) terminologies,

Figure 5 Photomicrograph showing histopathological examination of bone marrow biopsy showing significant eosinophilia. Arrows pointing to eosinophils. (H&E; 40×). Inayat F, et al. BMJ Case Rep 2018;11:e227137. doi:10.1136/bcr-2018-227137

Figure 6 CT scan of the chest showing ground-glass opacities in lungs without fibrosis. including ‘idiopathic hypereosinophilic syndrome’, '‘skin rash’ and ‘cutaneous’ were combined using the Boolean operators ‘AND’ and ‘OR’ with the terms ‘idiopathic HES’, ‘skin involvement’ and ‘HES treatment’. Furthermore, a few articles were retrieved through a manual search using the reference list of all accessible publications. The inclusion criteria for the final comparative analysis consisted of the articles available in the fulltext form in the English-language literature. A total of 143 articles consisting of but not limited to original articles, case series and case reports were initially obtained using the above-mentioned search strategy. The titles and abstracts of all these articles were carefully reviewed for their relevance to our study. A total of 37 articles were first enlisted for rereview while 106 studies were excluded as they were not related to cutaneous involvement secondary to idiopathic HES, were in a language other than the English, and/or full-text versions were not available. After removing duplicate and redundant articles, 25 papers were included in the present study for the final review and analysis. A thorough reading of these articles yielded a total of 32 cases of idiopathic HES with cutaneous involvement.5–29 A comprehensive review of these case reports indicated a slight male predominance (male, n = 19; female, n = 13). The mean age of patients was 39.54 years (range: 2.5–73 years). The mean initial eosinophil count was 7.7×109/L, ranging from 0.03×109/L to 52×109/L. The data of patients regarding the epidemiology, clinical features, diagnosis and management are summarised in tables 2.1 and 2.2. The common cutaneous presentation was pruritic, erythematous, oedematous, painful papular eruption on the extremities and/or trunk. Occasionally, concurrent atrophic changes and postinflammatory hyperpigmentation of the skin were also identified. Furthermore, superficial venous thrombophlebitis, palmar erythema, telangiectasia, lichenification of the hands and feet, and perioral/periorbital angio-oedema were among the other notable skin changes. In addition to cutaneous manifestations, these patients had concomitant symptoms related to other organ systems such as cardiorespiratory involvement with chronic cough, dyspnoea, orthopnoea, chest pain and signs of mitral regurgitation; neurological involvement with headache, light headedness, blurred vision, hyposthenia, paraesthesia and depressed consciousness; musculoskeletal involvement with fatigue, arthralgia, myalgia and multi-joint swelling, along with generalised findings related to inflammation such as fever, malaise, night sweats and weight loss. It was also notable that 3


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4


2003

2003

Fujii et al10

Fujii et al10

2000

Jang et al7

2003

2000

Jang et al7

Narayan et al9

1997

Bogenrieder et al6

2000

1987

Alfaham et al5

Yoon et al8

Publication year

Authors

Japan

Japan

UK

Korea

Korea

Korea

Germany

UK

Country

35/F

60/M

23/M

62/M

24/M

34/M

38/F

14/F

Age/ gender

3.06×109/L

5.2×109/L

Initial eosinophil count

9.3×109/L

2.68×109/L

8.58×109/L

Tender, infiltrated, erythematous plaque on the back

5.6×109/L

Multiple, tender, 16.0×109/L infiltrated, erythematous plaques on the abdominal skin, with itchy urticarial erythema

Dry cough, mild fever, and painful skin lesions on both lower legs causing difficulty in walking

Generalised skin lesions and chronic cough for 1 year

Pruritic, erythematous patches on both the legs and cyanosis of fingers

Pruritic, brown, 8.51×109/L erythematous, indurated patches and plaques on the lower extremities and periungual areas

Pruritic, erythematous, oedematous lesions over the trunk and lower legs, B-symptoms, and dyspnoea

Dyspnoea on minimal exertion, orthopnoea, and fine petechial rash

Clinical presentation

Treatment

Prednisolone 30 mg/day. Pentoxifylline 400 mg three times a day, and nifedipine 10 mg three times a day

Prednisolone 20–50 mg/ day; tapered to 30 mg/day. Pentoxifylline 400 mg three times a day, and nifedipine 10 mg three times a day

Prednisone 500 mg/day initially. Subsequently, oral prednisone 60 mg/day

Skin biopsy: infiltrating eosinophils and focal deposits between collagen fibres. Papillary dermal oedema and perivascular infiltration of eosinophils

Prednisone (1 mg/kg/day)

Skin biopsy: sheets of eosinophils Prednisone (0.5 mg/kg/day) infiltrating between collagen fibres and focal deposits of eosinophilic materials, suggestive of flame figures

Skin biopsy showed full-thickness Oral prednisone 60 mg/day, necrosis from epidermis to subcutis, and oral morphine 30 mg/day for thrombosis of medium-sized vessels, leg pain and eosinophilic infiltrates in the dermis. BMB showed hypereosinophilia

BMB showed eosinophilic hyperplasia. Oral prednisone, antihistamines, Endoscopic biopsy from the stomach systemic PUVA, triamcinolone, and duodenum showed chronic gastritis and interferon-α with metaplasia and eosinophilic infiltrates

Skin biopsy showed necrotising vasculitis of small vessels with a prominent infiltrate of eosinophils

Skin biopsy: necrotising vasculitis of small vessels with eosinophilic infiltrates. Subsequently, biopsy of a new axillary lesion also revealed eosinophilia. CT abdomen: multiple nodules in the liver. Doppler studies of both the extremities revealed multiple thrombi

Biopsy of bronchial mucosa showed granulomatous infiltration and eosinophilia. Endomyocardial biopsy revealed eosinophilic myocarditis

BMB and trephine showed pronounced Prednisone (2 mg/kg/ hypereosinophilia without malignant day), furosemide, folic acid, changes and warfarin

Diagnostic investigation findings

Table 2.1 Literature review (1987-2009) of idiopathic hypereosinophilic syndrome with cutaneous involvement Outcome

Remission

Remission

Remission

Continued

Skin lesions disappeared with treatment Remission but recurred on tapering steroids; therapy resumed at increased dose

Erythematous plaques, neuropathies and Remission epigastric pain resolved, but eosinophilia persisted. Recurrence of bronchospasm and urticarial lesions despite steroid therapy

On day 6 of admission, patient developed Remission DVT and was anticoagulated with LMWH followed by warfarin. His skin lesions and eosinophil count improved. He was discharged on prednisone and warfarin

Itching and skin lesions didn’t respond to steroids. Therapy was switched to interferon-α with complete recovery of skin, pulmonary and GI findings

Skin lesions and biochemical profile significantly improved with the combination therapy

Skin lesions and mononeuritis multiplex improved but after self-withdrawal of prednisone, digital gangrene of the right index finger developed and it was amputated. After treatment was reinitiated, hepatic nodules and axillary mass disappeared; ALT and eosinophil count decreased

Overall improvement with disappearance Remission of skin changes. Steroids tapered to 7.5 mg/day. Recurrence of the disease 1 year later, managed again with highdose steroids

Remission CCF improved, eosinophil count normalised and skin rash disappeared in 3 days. Relapsed (eosinophils: 1.5×109/L) in 2 weeks after steroid cessation, prednisone 10 mg on alternate days was reinitiated

Clinical course after treatment


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5

Publication year

2003

2004

2004

2005

2005

2006

2006

Authors

Fujii et al10

Martin et al11

Selvi et al12

Katz et al13

Amano et al14

Terrier et al15

Terrier et al15

Table 2.1 Continued

France

France

Japan

USA

Italy

Germany

Japan

Country

26/M

36/M

22/M

15/M

70/M

34/F

26/M

Age/ gender

Recurrent SVT

Erythematous, painful palpable venous cords in the lower extremities

Pigmented papules that initially appeared on legs and then, spread to entire body

Non-productive cough, night sweats, and diffuse pruritic papular rash

Acute knee arthritis, multi-joint swelling, fatigue, and weight loss. Oedematous, erythematous, urticarial, papular skin lesions

Abdominal pain, fatigue, dyspnoea, cough, SOB, signs of mitral regurgitation, systolic murmur, and skin rashes with pruritus

Pruritic, indurated, urticarial erythema in the left pretibial area


1.5×109/L

1.8×109/L

2.6×109/L

52.0×109/L

2.87×109/L

2.16×109/L

15.1×109/L

Initial eosinophil count Betamethasone (2 mg/kg/day)

Treatment

Methylprednisone, loratadine, mebendazole, montelukast, and ketotifen

Skin biopsy: thrombosis of dermal vessels with moderate reactive perivascular lymphocytic infiltration

Doppler USG confirmed SVT. Skin biopsy of the thigh lesion: thrombosis of a hypodermal venous wall with mild lymphocytic infiltrate (but no eosinophils). Clonal rearrangement of T-cell receptor γ was present. FIP1L1PDGFRα negative

Prednisone (30 mg/day), fluindione, interferon-α (3 million units thrice/week), and fluindione/ aspirin

Prednisone (40 mg/day), enoxaparin sodium, colchicine, fluindione, interferon-α (3 million units three times a week, and inhaled beclomethasone dipropionate

HRCT: ground-glass appearance of Topical steroids, PUVA therapy, right lower lung lobe. Lung biopsy: and oral prednisone vascular and interstitial eosinophilic infiltration. BMB: increased eosinophilic series with vacuolation and hyperplasia of megakaryocytes. Skin biopsy: perivascular eosinophils in dermis

Lung biopsy: patchy interstitial and Oral prednisone and imatinib intra-alveolar inflammation with eosinophils. Skin biopsy: neutrophilic folliculitis and perivascular eosinophils. BMB: hypercellular marrow with eosinophils

Synovial fluid aspirate from right knee was yellowish, 5000 WBCs/ mm3 with 20% eosinophils. Skin biopsy and histopathology of synovial tissue specimen showed perivascular eosinophilic infiltrates

Outcome

Remission

Remission

Remission

Continued

Multiple relapses after steroid tapering. Remission Interferon-α and prednisone rapidly improved. No subsequent relapse during 7 months of follow-up

SVT and eosinophilia recurred after steroid tapering; dose increased with colchicine and fluindione initiation. In 1 year,~10 relapses of eosinophilia (1.5×109/L) and SVT. Interferon-α dramatically regressed SVT; prednisone tapered (20% eosinophils

BMB smears showed increased eosinophil precursors and eosinophils (40%)

Prednisone, mycophenolate mofetil, methotrexate, and ciclosporine. Tofacitinib 5 mg two times per day

Prednisone, mycophenolate mofetil, and methotrexate. Ruxolitinib 25 mg in the morning and 10 mg at night

Methylprednisolone (2 mg/kg/ day)

Echocardiography: infiltrative Methylprednisone, hydroxyurea, myocarditis. BMB: prominant and imatinib mesylate eosinophilia. CT head and MRI: vasculitis of CNS

BMB and trephine: reactive eosinophilia with normal chromosomal and clonal studies. CTA and cardiac MRI: asymptomatic multianeurysmal CAD and a sinus of Valsalva aneurysm with thrombosis

MRI: acute myocarditis. BMB: hypercellular marrow with granulocyte hyperplasia, eosinophilia and mild multilineage dysplasia. Skin biopsy: eosinophilic infiltrates in dermis and flame figures

Clinical course after treatment Outcome

Remission

Excellent response to tofacitinib with resolution of skin lesions and no pruritus after 7 months of follow-up (eosinphilis: 0.08×109/L). Adverse reaction: episode of herpes simplex virus reactivation

Continued

Remission

No response to initial treatment. Remission Excellent response to ruxolitinib with no pruritus and erythema limiting to shins after 6 months of follow-up (eosinphilis: 0.3×109/L). Adverse reactions: UTI and furuncle

Complete response with Remission methylprednisolone in 3 months. Patient experienced two recurrences but she is alive and in good health after 108 months of follow-up

Neurological symptoms improved Remission but eosinophil count increased. Haemoglobin dropped from 10.9 g/dL to 6.7 g/dL. CT abdomen showed retroperitoneal bleeding due to vasculitis treated with embolisation. Imatinib 200 mg resolved eosinophilia in 2 days and dose reduced to 100 mg after 1 week

Patient responded well to oral steroids; cardiac manifestations were managed with surgery

Moderate improvement in Remission eosinophilia in 1 week. After 40 days, it resolved with complete recovery from myocarditis and cutaneous lesions


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ARDS, acute respiratory distress syndrome; BMB, bone marrow biopsy; CAD, coronary artery disease; CNS, central nervous system; CTA, CT angiography; CXR, chest X-ray; PET, positron emission tomography; SOB, shortness of breath; UTI, urinary tract infection; UV-B, ultraviolet-B.

Remission At the 1-month follow-up, he reported good response to high-dose oral prednisone with diminution of his symptoms. The dose was tapered to 7.5 mg/day without any flares Corticosteroids (1 mg/kg) 51/M 2018 The present report

USA

Diffuse skin rash, SOB, and facial swelling

3.5×109/L

BMB showed marked hypereosinophilia

Clinical course after treatment Outcome

Remission Tofacitinib resolved skin lesions and pruritus (eosinphilis: 0.58×109/L). No relapse after 7 months of follow-up. No adverse reactions

Treatment

Prednisone 10 mg/day. Tofacitinib 5 mg two times per day

Diagnostic investigation findings

1.5×109/L

Skin biopsy demonstrating infiltration of eosinophils. BMB showing >20% eosinophils


52/M King B et al29

Country

2017

Authors

USA

Eczematous dermatitis involving 50% of body surface area and moderate-severe pruritus

Initial eosinophil count Age/ gender Publication year

Table 2.2 Continued


As regards the treatment of cutaneous lesions, photochemotherapy with psoralen and ultraviolet A (PUVA) and topical steroids like mometasone can be useful in some patients.36 Selvi et al reported a case where montelukast and ketotifen provided significant relief from HES-related arthritis and rash.12 In rare instances, splenic or cardiac surgery may also be performed to improve organ function after proper evaluation.37 In this review, the treatment of skin lesions was mainly focused on oral or topical steroids and PUVA therapy in addition to other immunosuppressive agents. In a majority of patients, antihistamines were effective for pruritus and morphine for the pain relief. The treatment was also tailored in accordance with the organ system involvement such as diuretics like furosemide for fluid overload, anticoagulation with warfarin, and digitalis for cardiac symptoms. Although most of the patients included in this review achieved remission, a few also experienced recurrence. In cases with untreated HES, prognosis is generally poor, especially in patients with cardiac involvement. As the mortality and morbidity is high from cardiac complications, all patients with HES should undergo screening and surveillance for occult cardiac disease using echocardiography and ECG every 6 months.38 The FIP1L1/PDGFRA-associated fusion gene-positive patients show a good response to imatinib and a favourable prognosis while elevated tryptase levels show a poor response to imatinib, conferring a poor prognosis.39 Furthermore, patients with high serum IgE levels and angio-oedema usually show a good prognosis whereas leucocytosis, myeloblasts in blood and congestive cardiac failure are among the indicators of a poor prognosis in patients with HES.40

Learning points ►► Idiopathic hypereosinophilic syndrome (HES) is an uncommon

disorder marked by hypereosiophilia, without an obvious cause. ►► HES-related cutaneous lesions are usually pruritic, tender, erythematous and oedematous papules that are commonly encountered on the extremities but trunk involvement may also be noted. ►► Diagnostic workup is extensive and is focused on ruling out secondary causes of eosinophilia, evaluation of end-organ damage, and cytogenetic studies to assess the prognosis and response to therapy. ►► Treatment includes corticosteroids and/or immunosuppressive agents aiming to reduce peripheral eosinophil count and to prevent associated end-organ damage. Although asymptomatic patients do not require any treatment, cardiac function surveillance is of paramount importance for prompt detection of serious complications. ►► Physicians should maintain a high index of clinical suspicion for idiopathic HES in patients presenting with cutaneous lesions with concurrent hypereosinophilia, without any identifiable aetiology. Contributors FI: designed the study, performed the systematic literature review, drafted the manuscript, formulated the data table, revised the manuscript and gave the final approval for the version published. SSO: drafted and reviewed the manuscript. FZ: drafted the manuscript, performed the literature search, formulated the data table and contributed to the discussion. SM: revised the manuscript critically for important intellectual content. IV: reviewed the manuscript and suggested pertinent modifications. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors . Competing interests None declared. 9


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Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.

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Rare disease