Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases

Abstract

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 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

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 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.

Figure 1.

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

Figure 2.

Diffuse, papular rash involving the back.

Figure 3.

Cutaneous lesions consistent with erythematous plaques and papules on the left arm and forearm.

Investigations

The patient underwent an extensive diagnostic workup. The details of his laboratory evaluations are provided in table 1.

Table 1.

Initial laboratory investigations of the patient with respective reference ranges

Laboratory parameter	Specimen	Patient result	Reference range
White cell count	Serum	13.3×109/L	4.8–10.8×109/L
Red cell count	Serum	4.77×109/L	4.70–6.10×109/L
Haemoglobin	Serum	14.8	14–18 g/dL
Haematocrit	Serum	44.7	42.0%–52.0%
Platelets	Serum	2.44×109/L	1.5–4.5×109/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.

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 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.

Figure 4.

Photomicrograph of bone marrow biopsy demonstrating abundant eosinophils with no signs of malignancy or other abnormalities. (H&E; 20×).

Figure 5.

Photomicrograph showing histopathological examination of bone marrow biopsy showing significant eosinophilia. Arrows pointing to eosinophils. (H&E; 40×).

Figure 6.

CT scan of the chest showing ground-glass opacities in lungs without fibrosis.

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, 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, 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 full-text 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.

Table 2.1.

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

Authors	Publication year	Country	Age/ gender	Clinical presentation	Initial eosinophil count	Diagnostic investigation findings	Treatment	Clinical course after treatment	Outcome
Alfaham et al 5	1987	UK	14/F	Dyspnoea on minimal exertion, orthopnoea, and fine petechial rash	5.2×109/L	BMB and trephine showed pronounced hypereosinophilia without malignant changes	Prednisone (2 mg/kg/day), furosemide, folic acid, and warfarin	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	Remission
Bogenrieder et al 6	1997	Germany	38/F	Pruritic, erythematous, oedematous lesions over the trunk and lower legs, B-symptoms, and dyspnoea	3.06×109/L	Biopsy of bronchial mucosa showed granulomatous infiltration and eosinophilia. Endomyocardial biopsy revealed eosinophilic myocarditis	Prednisone 500 mg/day initially. Subsequently, oral prednisone 60 mg/day	Overall improvement with disappearance of skin changes. Steroids tapered to 7.5 mg/day. Recurrence of the disease 1 year later, managed again with high-dose steroids	Remission
Jang et al 7	2000	Korea	34/M	Pruritic, brown, erythematous, indurated patches and plaques on the lower extremities and periungual areas	8.51×109/L	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	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	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	Remission
Jang et al 7	2000	Korea	24/M	Pruritic, erythematous patches on both the legs and cyanosis of fingers	8.58×109/L	Skin biopsy showed necrotising vasculitis of small vessels with a prominent infiltrate of eosinophils	Prednisolone 30 mg/day. Pentoxifylline 400 mg three times a day, and nifedipine 10 mg three times a day	Skin lesions and biochemical profile significantly improved with the combination therapy	Remission
Yoon et al 8	2000	Korea	62/M	Generalised skin lesions and chronic cough for 1 year	2.68×109/L	BMB showed eosinophilic hyperplasia. Endoscopic biopsy from the stomach and duodenum showed chronic gastritis with metaplasia and eosinophilic infiltrates	Oral prednisone, antihistamines, systemic PUVA, triamcinolone, and interferon-α	Itching and skin lesions didn’t respond to steroids. Therapy was switched to interferon-α with complete recovery of skin, pulmonary and GI findings	Remission
Narayan et al 9	2003	UK	23/M	Dry cough, mild fever, and painful skin lesions on both lower legs causing difficulty in walking	9.3×109/L	Skin biopsy showed full-thickness necrosis from epidermis to subcutis, thrombosis of medium-sized vessels, and eosinophilic infiltrates in the dermis. BMB showed hypereosinophilia	Oral prednisone 60 mg/day, and oral morphine 30 mg/day for leg pain	On day 6 of admission, patient developed DVT and was anticoagulated with LMWH followed by warfarin. His skin lesions and eosinophil count improved. He was discharged on prednisone and warfarin	Remission
Fujii et al 10	2003	Japan	60/M	Multiple, tender, infiltrated, erythematous plaques on the abdominal skin, with itchy urticarial erythema	16.0×109/L	Skin biopsy: sheets of eosinophils infiltrating between collagen fibres and focal deposits of eosinophilic materials, suggestive of flame figures	Prednisone (0.5 mg/kg/day)	Erythematous plaques, neuropathies and epigastric pain resolved, but eosinophilia persisted. Recurrence of bronchospasm and urticarial lesions despite steroid therapy	Remission
Fujii et al 10	2003	Japan	35/F	Tender, infiltrated, erythematous plaque on the back	5.6×109/L	Skin biopsy: infiltrating eosinophils and focal deposits between collagen fibres. Papillary dermal oedema and perivascular infiltration of eosinophils	Prednisone (1 mg/kg/day)	Skin lesions disappeared with treatment but recurred on tapering steroids; therapy resumed at increased dose	Remission
Fujii et al 10	2003	Japan	26/M	Pruritic, indurated, urticarial erythema in the left pretibial area	15.1×109/L	Skin biopsy: eosinophils between collagen fibres and in focal deposits as flame figures	Betamethasone (2 mg/kg/day)	Severe abdominal pain and urticarial erythema after 2 months. Laparotomy showed necrotic areas in terminal ileum. Spontaneously subsided	Remission
Martin et al 11	2004	Germany	34/F	Abdominal pain, fatigue, dyspnoea, cough, SOB, signs of mitral regurgitation, systolic murmur, and skin rashes with pruritus	2.16×109/L	Cardiac MRI: endomyocardial fibrosis of mitral valve. Doppler USG: restrictive heart failure	Digitalis, enalapril, torsemide, spironolactone, peptidyl dipeptidase inhibitors, prednisone, and cyclophosphamide	Patient stopped treatment after a few weeks	Treatment discontinued
Selvi et al 12	2004	Italy	70/M	Acute knee arthritis, multi-joint swelling, fatigue, and weight loss. Oedematous, erythematous, urticarial, papular skin lesions	2.87×109/L	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	Methylprednisone, loratadine, mebendazole, montelukast, and ketotifen	Mild or no response to steroids, anthelmintics and antihistamines. Good response to montelukast and ketotifen with only mild and brief recurrences	Remission
Katz et al 13	2005	USA	15/M	Non-productive cough, night sweats, and diffuse pruritic papular rash	52.0×109/L	Lung biopsy: patchy interstitial and intra-alveolar inflammation with eosinophils. Skin biopsy: neutrophilic folliculitis and perivascular eosinophils. BMB: hypercellular marrow with eosinophils	Oral prednisone and imatinib	Recurrence of symptoms and eosinophilia with tapering of steroids, which was managed using a combination of steroids and imatinib	Remission
Amano et al 14	2005	Japan	22/M	Pigmented papules that initially appeared on legs and then, spread to entire body	2.6×109/L	HRCT: ground-glass appearance of right lower lung lobe. Lung biopsy: vascular and interstitial eosinophilic infiltration. BMB: increased eosinophilic series with vacuolation and hyperplasia of megakaryocytes. Skin biopsy: perivascular eosinophils in dermis	Topical steroids, PUVA therapy, and oral prednisone	Patient was discharged after 74 days of treatment with corticosteroid therapy consisting of prednisone 30 mg/day	Remission
Terrier et al 15	2006	France	36/M	Erythematous, painful palpable venous cords in the lower extremities	1.8×109/L	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. FIP1L1-PDGFRα negative	Prednisone (40 mg/day), enoxaparin sodium, colchicine, fluindione, interferon-α (3 million units three times a week, and inhaled beclomethasone dipropionate	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 (<10 mg/day). In 10 months, no relapse of SVT, and eosinophils <1.0 × 109/L. Beclomethasone resolved asthma and pulmonary micronodules	Remission
Terrier et al 15	2006	France	26/M	Recurrent SVT	1.5×109/L	Skin biopsy: thrombosis of dermal vessels with moderate reactive perivascular lymphocytic infiltration	Prednisone (30 mg/day), fluindione, interferon-α (3 million units thrice/week), and fluindione/aspirin	Multiple relapses after steroid tapering. Interferon-α and prednisone rapidly improved. No subsequent relapse during 7 months of follow-up	Remission
Terrier et al 15	2006	France	59/M	Acrocyanosis	3.9×109/L	Doppler USG: bilateral SVT of the lower limbs and arterial thrombosis of the upper limbs. Skin biopsy: a dermal and subcutaneous infiltrate of eosinophils and vascular hyperplasia of a few vessels. Increased activated T cells	An initial pulse of methylprednisolone followed by oral prednisone (80 mg/day), and fluindione/aspirin	Initial treatment improved arterial and venous thrombosis and eosinophil count normalised. Transient eosinophilia (0.8×109/L) after dose tapering to 5 mg/day, but it was reversed with 10 mg/day. No relapse occurred thereafter	Remission
Prasad et al 16	2009	India	12/F	Fever, skin rashes, and swelling of knee and wrist joints	6.4×109/L	CXR: pericardial effusion and obliteration of cardiophrenic angle. BMB: eosinophilia. Cardiac biopsy: hypertrophic myocardial fibres, eosinophilic infiltrates and interstitial fibrosis. Skin biopsy: dermal infiltration of lymphocytes, plasma cells and a few eosinophils	Oral prednisone	Steroid cessation resulted in recurrence of the disease that was managed with reinstitution of steroids and then low-dose steroid maintenance therapy on alternate days	Remission

ALT, alanine aminotransferase; BMB, bone marrow biopsy; CCF, congestive cardiac failure; CXR, chest X-ray; DVT, deep venous thrombosis; GI, gastrointestinal; HRCT, high-resolution CT; LMWH, low-molecular-weight heparin; PUVA, psoralen and ultraviolet A; SOB, shortness of breath; SVT, superficial venous thrombophlebitis; USG, ultrasonography; WBC, white blood cell.

Table 2.2.

Literature review (2010-2018) of idiopathic hypereosinophilic syndrome with cutaneous involvement

Authors	Publication year	Country	Age/ gender	Clinical presentation	Initial eosinophil count	Diagnostic investigation findings	Treatment	Clinical course after treatment	Outcome
Preda et al 17	2010	Australia	41/M	Chronic pruritic eruption	2.2×109/L	Skin biopsy showed dermal and perivascular eosinophilic infiltrates with dermal oedema	Oral prednisone, mometasone cream, and antihistamines	Good response to steroids, antihistamines and topical therapy	Remission
Sundaramurthi et al 18	2011	India	33/F	Chronic itchy erythematous skin lesions	6.0×109/L	Peripheral smear: eosinophilia. BMB: normal eosinophil precursors. Skin biopsy: dermal mixed-cell granuloma	Steroids	Complete resolution of skin lesions in 1 week. Absolute eosinophil count normalised	Remission
Kim et al 19	2010	Korea	41/M	Painless digital gangrene with bony exposures. Brownish eczema-like patches and lichenification involving extremities	9.9×109/L	CT chest: ground-glass opacities on both lower lung fields. CTA: no vascular occlusion. Skin biopsy: marked dermal eosinophilic infiltration with necrotising eosinophilic vasculitis of a dermal vessel and prominent luminal microthrombus. The patient refused BMB	The patient refused treatment	The plan was to initiate corticosteroid therapy; however, he refused the treatment	No treatment
Howard et al 20	2012	USA	39/F	Blurred vision, urticarial skin rash, light headedness, and SOB	0.03×109/L	BMB: eosinophilic hyperplasia. Retinoscopy: dilated fundus, cotton-wool spots, haemorrhages, Purtscher flecken, reduced visual acuity and colour vision. Skin biopsy: perivascular lymphocytic infiltrate with mature eosinophils	Oral steroids	Retinopathy, visual acuity and colour vision improved. Eosinophil count normalised. Visual fields remained severely constricted	Remission
Powell et al 21	2013	UK	64/F	Pruritic eruption on the trunk and limbs	4.12×109/L	Skin biopsy: perivascular eosinophilic infiltration in dermis and flame figures	Oral steroids	Patient relapsed when steroids were stopped	Relapsed
Carlsen et al 22	2013	Denmark	64/F	Numerous uniform erythematous papules on the trunk and extremities. Erythema and hyperkeratosis of soles and palms	3.7×109/L	Skin biopsy: perivascular lymphocytic infiltrates reaching into the subcutaneous layer with eosinophilia and a few plasma cells. PET scan: multiple enlarged lymph nodes multifocally above and below the diaphragm. BMB: eosinophilia	A short course of high-dose systemic prednisolone followed by low-dose systemic prednisolone. Eventually, high-dose systemic prednisolone	Initial relief with empirical prednisolone but rapid relapse on discontinuation, managed with low-dose steroids. Readmitted with ARDS and eosinophilia (10.34×109/L), treated with high-dose therapy. All symptoms resolved (eosinophils: 0.12×109/L)	Remission
Wang et al 23	2014	China	47/M	Fever, cough, chest pain, and SOB. Small cutaneous erythematous nodules on the right chest wall	0.82×109/L	CXR: bilateral pneumothorax. CT: a focal opacity in the left lower lung and bilateral pleural effusions. Skin biopsy: eosinophilic infiltration into fibroadipose tissue. BMB: active proliferation of marrow cells, with eosinophilia. FIP1L1-PDGFRα negative	Oral prednisolone 1 mg/kg/day. Maintenance therapy with oral prednisolone	Closed thoracic drainage relieved pneumothorax. 1 week after therapy, eosinophilia dropped from 7.75×109/L to 1.95×109/L and lung opacities resolved. After 4 weeks, the eosinophil count was 0.04×109/L. All symptoms resolved after 2 months	Remission
Mahajan et al 24	2014	India	54/M	Pruritus, erythematous exfoliation, mild oedema of extremities, dry coarse skin of the hands and feet, and hyperkeratosis of palms and soles with honeycomb appearance	2.07×109/L	Skin biopsy: epidermal hyperplasia, acanthosis, paillomatosis, spongiosis and papillary oedema, suggestive of chronic spongiotic dermatitis with dermal inflammatory infiltrates of lymphocytes, eosinophils and a few histiocytes. BMB: myelopoiesis with 11% eosinophils, FIP1L1-PDGFRα negative	Oral ivermectin, albendazole, azithromycin, methotrexate, desloratidine and hydroxyzine. Hydroxycarbamide (500 mg twice a day), prednisolone (40 mg/day), then on alternate days, antihistamines, and emollients	No response to 12 weeks of initial treatment (eosinophils: 3.3×109/L). After 12 weeks of hydroxycarbamide and prednisolone treatment, pruritus subsided and a significant improvement in erythroderma was noted	Remission
Smith et al 25	2015	USA	40/F	Chest pain, SOB, B-symptoms, and erythematous, irregular, indurated, tender papules on the lower back and abdomen	28.4×109/L	MRI: acute myocarditis. BMB: hypercellular marrow with granulocyte hyperplasia, eosinophilia and mild multilineage dysplasia. Skin biopsy: eosinophilic infiltrates in dermis and flame figures	Refractory eosinophilia to high-dose steroids. Hydroxyurea 500 mg/day	Moderate improvement in eosinophilia in 1 week. After 40 days, it resolved with complete recovery from myocarditis and cutaneous lesions	Remission
Merika et al 26	2016	UK	30/F	Itchy papular eruption with postinflammatory hyperpigmentation on torso, arms and groin	7.3×109/L	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	Topical steroids, UV-B therapy, oral prednisone, hydroxycarbamide, and cardiac surgery scheduled	Patient responded well to oral steroids; cardiac manifestations were managed with surgery	Remission
Fraticelli et al 27	2016	Italy	51/M	Fatigue, weight loss, musculoskeletal pain, cutaneous infiltrated nodules, dyspnoea and elevated cardiac enzymes	25.9×109/L	Echocardiography: infiltrative myocarditis. BMB: prominant eosinophilia. CT head and MRI: vasculitis of CNS	Methylprednisone, hydroxyurea, and imatinib mesylate	Neurological symptoms improved 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	Remission
Tavil et al 28	2016	Turkey	2.5/F	Fever, malaise, headache, and abdominal pain. Skin rash and itching in her hands and feet	3.6×109/L	BMB smears showed increased eosinophil precursors and eosinophils (40%)	Methylprednisolone (2 mg/kg/day)	Complete response with methylprednisolone in 3 months. Patient experienced two recurrences but she is alive and in good health after 108 months of follow-up	Remission
King B et al 29	2017	USA	44/M	Erythematous, oedematous plaques involving the chest, abdomen, forearms, and lower legs. Severe pruritus	2.1×109/L	Skin biopsy: infiltration of eosinophils. BMB: >20% eosinophils	Prednisone, mycophenolate mofetil, and methotrexate. Ruxolitinib 25 mg in the morning and 10 mg at night	No response to initial treatment. 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	Remission
King B et al 29	2017	USA	73/F	Eczematous dermatitis involving 95% body surface area and severe pruritus	1.9×109/L	Skin biopsy: infiltration by eosinophils. BMB showing >20% eosinophils	Prednisone, mycophenolate mofetil, methotrexate, and ciclosporine. Tofacitinib 5 mg two times per day	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	Remission
King B et al 29	2017	USA	52/M	Eczematous dermatitis involving 50% of body surface area and moderate-severe pruritus	1.5×109/L	Skin biopsy demonstrating infiltration of eosinophils. BMB showing >20% eosinophils	Prednisone 10 mg/day. Tofacitinib 5 mg two times per day	Tofacitinib resolved skin lesions and pruritus (eosinphilis: 0.58×109/L). No relapse after 7 months of follow-up. No adverse reactions	Remission
The present report	2018	USA	51/M	Diffuse skin rash, SOB, and facial swelling	3.5×109/L	BMB showed marked hypereosinophilia	Corticosteroids (1 mg/kg)	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	Remission

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.

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 a majority of patients had comorbid conditions like allergy, asthma, hay fever and atopy.

The diagnosis of HES is based on the exclusion of probable secondary causes of eosinophilia and the assessment of end-organ damage. It frequently poses a diagnostic challenge due to a wide spectrum of aetiologies of eosinophilia such as infections, parasites, malignancy, vasculitis and other disorders with similar clinical and biochemical profiles.³⁰ The diagnostic workup for the evaluation of end-organ damage includes liver enzymes, creatine kinase, troponins, renal function testing, ECG, echocardiography, pulmonary function tests, CT scan, BMB with cytogenetics and fluorescence in situ hybridisation, MRI of brain, and skin biopsy.³¹ If the clinical condition of the patient is critical, diagnostic workup can be delayed in favour of empirical treatment.

In this review, an extensive diagnostic workup was performed to rule out possible secondary causes of eosinophilia. In a majority of patients, elevated IgE levels were noted. BMB showed eosinophilia without any evidence of malignancy or other haematological disorders. Cardiac biopsy revealed endomyocardial eosinophilic infiltrates with interstitial fibrosis. Echocardiography was notable for septal akinesia and tricuspid or aortic regurgitation. A few unexpected findings were also present in these patients that were mostly detected by different imaging modalities. Chest radiography in one patient showed pericardial effusion with obliteration of cardiophrenic angle while another patient presented with bilateral tension pneumothorax and pleural effusion. Cardiac MRI detected findings like endomyocardial fibrosis of mitral valve, an asymptomatic multianeurysmal coronary artery disease, a sinus of Valsalva aneurysm with thrombosis and acute myocarditis. CT and MRI of brain demonstrated vasculitic changes. Gastrointestinal endoscopy with biopsy showed gastritis with eosinophilic infiltrates and metaplasia. In most patients, skin biopsy revealed perivascular eosinophilic infiltration, dermal oedema and flame figures due to eosinophilic degranulation.

The therapeutic target in patients with HES is to decrease the absolute eosinophil count and prevention of progression of the disease.³² The assessment of the urgency of the therapy is the first step in management. Asymptomatic patients usually are not candidates for any treatment.³³ In cases with mild-to-moderate symptoms, therapy is mainly based on oral corticosteroids. Oral prednisone 1 mg/kg/day is administered for 2 weeks. Subsequently, it is tapered and then stopped over next 8 weeks. For isolated cutaneous involvement, the dose can be lowered to 0.5 mg/kg/day. Those who develop life-threatening complications like cardiac and neurological manifestations are treated with high-dose intravenous steroids, such as methylprednisone 1 mg/kg/day.³³ Steroid-sparing immunosuppressive drugs such as imatinib, hydroxyurea, interferons, etoposide, chlorambucil or vincristine are administered in patients who are refractory to steroids or experience recurrent episodes of disease. Mepolizumab, an anti-IL-5 antibody, is a novel therapy in addition to steroids for patients with HES who are negative for FIP1L1/PDGFRA while imatinib is the mainstay of treatment for mutation-positive patients.^{3 34} Similarly, King et al used Janus kinase (JAK) inhibitors, tofacitinib and ruxolitinib, demonstrating an excellent clinical response in three patients with idiopathic HES-related cutaneous involvement who were refractory to other treatments.²⁹ Plasmapheresis may not have any beneficial effects unless the patient has a high blood viscosity or a history of vaso-occlusive disease. The concomitant use of anticoagulant and antiplatelet agents is also important in selected patients.³⁵

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.