Syndrome of hyperimmunoglobulinemia E with recurrent infections: symptoms, diagnosis, treatment

Hyper-IgE syndrome (HIES) (0MIM 147060), formerly called Job syndrome, is characterized by recurrent infections, mainly of staphylococcal etiology, gross facial features, skeletal anomalies and a sharply elevated level of immunoglobulin E. The first two patients with a similar syndrome are described in 1966, Davis and colleagues. Since then, more than 50 cases with a similar clinical picture have been described, but the pathogenesis of the disease has not been determined to date.

Pathogenesis

The molecular genetic nature of HIES is not currently established. Most cases of HIES are sporadic, many families have autosomal dominant, and in some, autosomal recessive inheritance. Recent studies have shown that the gene responsible for the formation of the autosomal dominant variant of HIES is located on chromosome 4 (in the proximal 4q region), but this trend is not traced in families with recessive inheritance.

Numerous studies on the determination of immunological defects in HIES revealed abnormalities in neutrophil chemotaxis, decreased production and response to cytokines such as IFNr and TGFb, a specific response to T-dependent antigens such as Candida, diphtheria and tetanus toxoid. Many data support the presence of a defect in T-regulation, in particular, causing excessive production of IgE. However, the high concentration of IgE alone does not explain the increased susceptibility to infections, since some atopic individuals have similarly high levels of IgE, but do not suffer from severe infections characteristic of HIES. In addition, patients with HIES showed no correlation of IgE level with severity of clinical manifestations.

Symptoms

HIES is a multisystem disease, with various manifestations of dysmorphic and immunological disorders.

Infectious manifestations

Typical infectious manifestations of HIES are abscesses of the skin, subcutaneous tissue, furunculosis, pneumonia, otitis and sinusitis. Purulent infections in HIES patients are often characterized by a "cold" course: there is no local hyperemia, hyperthermia and pain syndrome. Most cases of pneumonia have a complicated course; in 77% of cases after pneumonia transferred pneumocoelis is formed, which can be mistakenly interpreted as polycystic pulmonary disease. The most frequent causative agent of infections is Staphylococcus aureus. In addition, there are infections caused by Haemophilus influenzae and Candida. Pneumatic targets can be infected with Pseadomonas aeruginosa and Aspergillus fumigatus, which complicates their therapy.

Chronic candidiasis of mucous and nails occurs approximately in 83% of cases. A rare infectious complication of HIES is pneumonia caused by Pneumocystis carinii, as well as visceral and disseminated pulmonary candidiasis, candidal endocarditis, cryptococcal lesions of the gastrointestinal tract and cryptococcal meningitis, mycobacterial infections (tuberculosis, BCGitis).

Noninfectious manifestations

The vast majority of patients with HIES have different skeletal anomalies:

• characteristic specific features of the face (hypertelorism, broad bridge of nose, broad snub nose, asymmetry of the facial skeleton, protruding forehead, deeply planted eyes, prognathia, high sky). A characteristic facial phenotype is formed in practically all patients to pubertal age;
• scoliosis;
• hypermobility of the joints;
• osteoporosis, as a consequence of a tendency to fracture of the bones after minor injuries;
• dysplasia of teeth (later eruption of milk teeth and a significant delay or lack of independent dental replacement).

Skin lesions resembling atopic dermatitis of moderate and severe course are present in many patients, often from birth. However, in patients with HIES, atypical localization of dermatitis occurs, for example, on the back or scalp. Respiratory manifestations of allergy are not found,

There is no reliable information on the predisposition of patients with HIES to autoimmune and neoplastic diseases, but cases of development of systemic lupus erythematosus, systemic vasculitis, lymphoma, chronic eosinophilic leukemia, and adenocarcinoma of the lung are described.

Diagnostics

Due to the absence of identified genetic defects, the diagnosis is made on the basis of a combination of a typical clinical picture and laboratory data. Characteristic is an increase in IgE above 2000 ME, patients with an IgE level of up to 50000 are described. Practically all patients have eosinophilia (often since birth); as a rule, the number of eosinophils exceeds 700 cells / mm3. With age, serum IgE concentrations and the amount of peripheral blood eosinophils can be significantly reduced. In most patients, a disturbance in the production of postvaccinal antibodies is determined. The number of T and B lymphocytes is usually normal, often a decrease in the number of CD3CD45R0 + lymphocytes.

Treatment

Pathogenetic therapy HIES has not been developed. The use of virtually any prophylactic antistaphylococcal antibacterial therapy prevents the onset of pneumonia. To treat infectious complications, including, and such as abscesses of the skin, subcutaneous tissue, lymph nodes and liver, prolonged parenteral antibacterial and antifungal therapy is used.

Surgical treatment of abscesses is rarely used. However, for a long time (more than 6 months) formed pneumocoel, surgical treatment is recommended, due to the risk of secondary infection or compression of organs.

To treat dermatitis, topical agents are used, in severe cases - low doses of cyclosporine A.

There is limited experience with bone marrow transplantation in patients with HIES, but it was not very encouraging - all patients experienced a relapse of the disease.

Immunotherapy, such as intravenous immunoglobulin and IFNr, also did not show clinical effectiveness with HIES.

Forecast

With the use of preventive antibacterial therapy, patients survive to adulthood. The main goal of therapy is the prevention of chronic lung lesions that are of a disabling nature.