Hyper-IgE syndrome (HIES) (Job’s syndrome) is characterized by elevated IgE levels and hypereosinophilia with a variable presentation based on organ involvement. There are two types: autosomal dominant (AD) and autosomal recessive (AR). The dominant form is associated with signal transducer and activator of transcription 3 (STAT3) mutation and is characterized by eczema, recurrent skin infection, pulmonary abnormalities, connective tissue, and heart and skeletal involvement. The genetic mutation of the recessive form is still unknown. Although in literature, dedicator of cytokinesis 8 (DOCK8) deficiency has been associated with the recessive form. It presents with a frequent viral infection and neurological abnormalities without somatic features.[2-4] The diagnosis of HIES is made by a scoring system, developed by the National Institute of Health.
We are describing a 6-year-old female child of HIES with recalcitrant eczema which did not respond to conventional systemic and topical agents. The eczematous lesions were subsequently controlled with injection omalizumab.
A 7-year-old female child born to nonconsanguineous marriage with full-term normal vaginal delivery presented with itchy oozy papulovesicular lesions all over the body for 1 year of age. There was a history of bilateral ear discharge along with growth retardation. The mother gave a history of recurrent furuncles with fever since childhood. Recurrent episode of pneumonia led to repeated hospitalization. The patient took various treatments in the form of oral and topical steroids (variable course and dose) and antibiotics for 5 years with partial response and without any remission.
The general examination revealed mild pallor with tender cervical and axillary lymphadenopathy. The patient had coarse facial features such as a high-arched palate, retention of primary teeth, pigmentation over the lip and buccal, broad nose, rough skin on the face, and prominent forehead. Height and weight were 107 cm (below 5th percentile) and 23.6 kg (50th percentile), respectively [Figure 1].
On mucocutaneous examination, the patient was in erythroderma with papules, vesicles, and nodules with widespread areas of lichenification present over extremities, trunk, and face [Figure 2]. In addition, there were multiple furuncles over the trunk and extremities. Routine hematological investigation showed increased Total leukocyte counts TLC of value 20210 cells/mm3 with eosinophilia constituting 26%, IgE ‒ 3480 IU/ml, and an absolute eosinophil count on peripheral blood smear 2990 cell/mm3. Culture from the furuncle showed Staphylococcus aureus, and ear discharge showed Escherichia coli. Chest X-ray was normal.
The patient was finally diagnosed with AD-HIES with a total score of 38 [Table 1]. The genetic studies could not be done due to the nonavailability of the facility. The patient was started with antibiotics based on the culture sensitivity report along with a bleach bath and emollients. Following the resolution of furuncles and no evidence of pneumonia, oral prednisolone 1 mg/kg/day was started for eczematous skin lesions. Despite 3 weeks of oral prednisolone, there was a minimal improvement of eczema. Subsequently, the patient was switched to oral cyclosporin 5 mg/kg/day and the oral steroid was subsequently tapered. There was around 30%–40% improvement in eczematous skin lesions following the addition of cyclosporine after 2 weeks of oral steroid for 3 months. The oral steroid was stopped in view of stunted growth of the child, puffiness of the face, and variable dose of treatment with same in past for prolonged periods. The eczematous lesions recurred back with increased severity of oozing from the face and trunk despite cyclosporin 5 mg/kg/day. Repeat investigations showed absolute eosinophil count on peripheral blood smear increased to 2030 cell/mm3 but IgE reduced to 1038 IU/ml as compared to baseline. In view of minimal response in eczematous skin lesions to prolong and variable coarse of oral steroid and cyclosporin, injection omalizumab at 150 mg was given at every 2-week interval. After three doses of injection omalizumab, there was control of skin lesions in the form of the absence of new skin lesions with 70%–80% improvement of lichenification [Figures 3-5]. After four doses at 2-week interval, the patient was shifted to monthly injection omalizumab. Due to financial issues, fifth dose of omalizumab could be given. The patient was maintained on tapering dose of oral steroid, thalidomide, azathioprine, and antihistamine and kept under follow-up for reoccurrence of lesions.
HIES is a rare group of primary immunodeficiency diseases which is characterized by the triad of increased IgE levels, recurrent skin abscess, and pneumonia. David et al. first described HEIS as Job’s syndrome in 1966 which involve multisystem organ, i.e., teeth, skeletal, connective tissue, skin, lungs, and immunity. Mutations in the STAT3 gene causes AD-HIES, whereas mutations and deletions in tyrosine kinase 2 and DOCK8 cause AR-HEIS.
More than 200 cases have been reported to date. Males and females are affected equally and occur in all ethnic groups. It involves the age group ranging from 0 to 60 years. The first symptom is rash at birth or early infancy, which evolves into eczematous skin lesions affecting the face, trunk, and extremities. Severe pruritus leads to excoriation, followed by lichenification. Recurrent bacterial skin abscesses and ear and sinus infections are common, with S. aureus being the most common causative organism. The patient may develop recurrent mucocutaneous candidiasis. Recurrent pyogenic pneumonia starts in childhood and is frequently caused by S. aureus, Streptococcus pneumonia, and Haemophilus species.
Skeletal and connective tissue involved in the form of the prominent forehead, high-arched palate, broad nose, cleft lip and palate (facial asymmetry), osteoporosis, frequent fractures following trauma, scoliosis, and joint hyperextensibility. Retention of primary teeth occurs due to reduced resorption.
Treatment of HIES is largely supportive which includes bleach baths, prophylactic antibiotics (for recurrent skin and ear infections), antifungal (for mucocutaneous candidiasis), oral and topical steroids, and cyclosporin (for eczematous oozy skin lesions). Bone marrow transplantation has also been tried with limited success. Despite all treatment modalities, patients had developed recurrently eczematous and secondary infection skin lesions. Omalizumab, the humanized monoclonal antibody against IgE also downregulates IgE receptors and cytokines (interleukin-2 (IL) and IL-13) and increases apoptosis of eosinophil. Elevated IgE levels in HIES do suggest the role of omalizumab in the management of HIES, however, there is no literature mentioning the guidelines. Limited case series have shown the benefit of omalizumab in HIES but no longitudinal/follow-up study regarding the dose and duration of treatment required for complete remission exists in the literature.
The aim of managing cases of HIES is to control skin lesions as patients have continuous itching, which leads to trauma to the skin, so secondary infections occur with the itch-scratch cycle. Hence, it is essential to control this cycle.
In our case, there was a recurrence of skin and ear infections despite oral prednisolone and cyclosporin along with oral antibiotics and bleach baths. Our patient received 150 mg of injection omalizumab at 2-week interval. There was a direct correlation of decrease in skin oozy lesions along with IgE level ‒76 IU/ml, absolute eosinophil count ‒320 cell/mm3, and SCORAD score (40.3) following injection omalizumab. Hence, we suggest omalizumab can be an effective treatment option in eczematous skin lesions of HIES.
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The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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