Hyperimmunoglobulinemia E syndrome with recurrent infections: symptoms, diagnosis, treatment

Hyper-IgE syndrome (HIES) (0MIM 147060), previously called Job syndrome, is characterized by recurrent infections, predominantly of staphylococcal etiology, coarse facial features, skeletal abnormalities, and markedly elevated levels of immunoglobulin E. The first two patients with this syndrome were described in 1966 by 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 yet been determined.

Pathogenesis

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

Numerous studies investigating the immunological defects in HIES have found abnormalities in neutrophil chemotaxis, decreased production of and response to cytokines such as IFNr and TGFb, and impaired specific response to T-dependent antigens such as Candida, diphtheria, and tetanus toxoids. Much evidence supports a defect in T regulation, particularly one that causes excessive IgE production. However, high IgE levels alone do not explain the increased susceptibility to infections, as some atopic individuals have similarly high IgE levels but do not suffer from the severe infections characteristic of HIES. In addition, IgE levels do not correlate with the severity of clinical manifestations in patients with HIES.

Symptoms

HIES is a multisystem disorder with varying degrees of dysmorphic and immunological abnormalities.

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, pneumoceles are formed after pneumonia, which can be mistakenly interpreted as polycystic lung disease. The most common causative agent of infections is Staphylococcus aureus. In addition, infections caused by Haemophilus influenzae and Candida are noted. Pneumoceles can be infected with Pseadomonas aeruginosa and Aspergillus fumigatus, which complicates their treatment.

Chronic candidiasis of the mucous membranes and nails occurs in approximately 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 gastrointestinal tract infection and cryptococcal meningitis, mycobacterial infections (tuberculosis, BCG).

Non-infectious manifestations

The vast majority of patients with HIES have various skeletal abnormalities:

• characteristic specific facial features (hypertelorism, wide nasal bridge, wide snub nose, facial skeletal asymmetry, prominent forehead, deep-set eyes, prognathism, high palate). The characteristic facial phenotype is formed in almost all patients by puberty;
• scoliosis;
• joint hypermobility;
• osteoporosis, resulting in a tendency to bone fractures after minor injuries;
• disturbances in the change of teeth (late eruption of milk teeth and significant delay or absence of independent change of teeth).

Skin lesions resembling moderate to severe atopic dermatitis are present in many patients, often from birth. However, patients with HIES have atypical locations of dermatitis, such as the back or scalp. Respiratory manifestations of allergy are not observed.

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

Diagnostics

Since no genetic defects have been identified, the diagnosis is based on a combination of the typical clinical picture and laboratory data. IgE levels above 2,000 IU are characteristic; patients with IgE levels up to 50,000 have been described. Almost all patients have eosinophilia (often from birth); as a rule, the number of eosinophils exceeds 700 cells/μl. With age, serum IgE concentrations and the number of peripheral blood eosinophils may decrease significantly. Most patients have impaired post-vaccination antibody production. The number of T and B lymphocytes is usually normal; a decrease in the number of CD3CD45R0+ lymphocytes is often observed.

Treatment

Pathogenetic therapy for HIES has not been developed. The use of virtually any prophylactic antistaphylococcal antibacterial therapy prevents the occurrence of pneumonia. Long-term parenteral antibacterial and antifungal therapy is used to treat infectious complications, including abscesses of the skin, subcutaneous tissue, lymph nodes and liver.

Surgical treatment of abscesses is rarely used. However, in case of long-standing (more than 6 months) pneumoceles, surgical treatment is recommended due to the risk of secondary infection or compression of organs.

Dermatitis is treated with topical agents, and in severe cases, low doses of cyclosporine A.

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

Immunotherapy agents such as intravenous immunoglobulin and IFNr have also not been shown to be clinically effective in HIES.

Forecast

With the use of prophylactic antibacterial therapy, patients survive to adulthood. The main goal of therapy is the prevention of chronic lung damage that is disabling in nature.