SUMMARY

 

1.  Hyper IgE Syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses, recurrent pneumonia, eczematous dermatitis, and elevated serum IgE levels (usually over 2,000 IU/ml).  

 

2.  Recurrent Staph aureus skin abscesses and pneumonias are the most common infectious complications encountered by patients.  Sinopulmonary infections from Strep pneumoniae and Haemophilus influenzae can also occur.  Pneumonias can be complicated by pneumatocele formation - these may become superinfected by Pseudomonas and Aspergillus.  Additionally, patients can develop chronic mucocutaneous candidiasis involving the oral mucosa/nails and rare cases of Pneumocistis jirovecii infection have been reported.  

 

3.  The exact mechansim of immunodeficiency in HIES has not been elucidated but appears to be the result of impaired differentiation of IL-17 secreting T-cells.  IL-17 is important in the extracelluar defense against bacteria and fungi.     

 

4.  Laboratory findings include elevated IgE and eosinophilia.  Elevated IgE does not correlate with severity of disease.  Total immunoglobulin levels are normal or elevated but patients may have poor response to protein and polysaccharide immunizations.  Neutrophil killing is intact but neutrophil chemotaxis is often impaired.  Decreased Th17 cell numbers are found in both AD and AR forms of disease.     

 

Autosomal Dominant (STAT3) - This accounts for the majority (70%) of patients with HIES and is characterized by the following features:

      •  Severe Eczema
      •  Recurrent bacterial skin abscesses and pneumonias
      •  Pneumatoceles
      •  Coarse facial features - wide nose, deep-set eyes, prominent chin and     forehead
      •  Delayed shedding of primary teeth 
      •  Pathologic fractures
      •  Scoliosis
      •  Joint hypermobility

 

Autosomal Recessive (DOCK8) - This form of HIES had been described in >30 patients and is characterized by the following clinical features: 

      •  Severe Eczema
      •  Recurrent bacterial skin abscesses and pneumonias
      •  No recurrent fractures, no joint hypermobility, and no  pneumatoceles.  Retained primary teeth has been 
         reported (Engelhardt JACI 2009).
      •  Viral cutaneous infections (Molluscum, Herpes simplex, HPV)
      •  Combined immunodeficiency  decreased T cell numbers and function, low IgM, elevated IgG, and           
          variable specific antibody responses.

 

Autosomal Recessive (Tyk2) - Two patients with Tyk2 deficiency have been reported.  The first patient was characterized by eczema, skin abscesses, pneumonias, viral skin infections, and intracellular bacterial infections (salmonella, BCG).   A second patient with a milder phenotype was recently reported.  

 

6.  There appears to be an increased risk of developing lymphoma as well as coronary artery dilation and aneurysms in AD HIES.  

 

7.  This diagnosis should be suspected in patients with characteristic infections, pneumatoceles (AD),  musculoskeletal findings (AD), and elevated IgE levels.  Elevated IgE is a non-specific finding and can be elevated in patients with other atopic disease such as asthma or eczema.  The presence of invasive skin and lung infections helps to distinguish HIES from atopic dermatitis with elevated IgE.  

 

8.  A scoring system developed by the National Institutes of Health (NIH) is a useful tool for quantifying the clinical and laboratory features of suspected patients.  Using this scoring system, most autosomal dominant HIES patients have a score above 40.   

 

9.  STAT3 gene sequencing is now commercially available for patients who have suggestive clinical and laboratory findings.  Tyk2 and DOCK8 testing is currently available only at specialized research centers.

 

10.  Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component) is useful for preventing staphylococcal infections.  Effective care of dermatitis can help to maintain the skin barrier and prevent infections.  Patients with chronic mucocutaneous candidiasis may benefit from antifungal prophylaxis (ex.  Itraconazole 5mg/kg once daily).  Patients with specific antibody deficiency may benefit from IVIG replacement therapy.  

 

 

 

                                                                                                            

OVERVIEW

 

     Hyper IgE Syndrome (HIES) is a multi-system disease characterized by recurrent staphylococcal skin abscesses, pneumonia with pneumatocele formation, eczematous dermatitis, and elevated serum IgE levels (usually over 2,000 IU/ml).   Both autosomal dominant and autosomal recessive forms of disease have been described and differ significantly in their clinical features.  

 

     Patients have an increased susceptibility to cutaneous and pulmonary bacterial infections.  Staphylococcus aureus is the most common pathogen causing skin and pulmonary infections.  Steptococcus pneumoniae and Haemophilus influenzae are important pathogens causing pneumonia.  Patients often develop pneumatoceles following  pneumonias.  Secondary infection of pneumoatoceles by Pseudomonas and Aspergillus can occur.  While patients are generally not at risk for serious opportunistic infections, chronic mucocutaneous candidiasis involving the oral mucosa and nails (causing dystrophic changes) may occur.  Rare cases of pulmonary infections with Pneumocystis Jiroveci have been reported.

 

     Autosomal dominant HIES (STAT3) is characterized by recurrent infections, eczema, and a unique set of somatic findings.  Patients have characteristic coarse facial features including a broad nasal base/nasal bridge as well as frontal bossing, deep set eyes, and prominent chin.  Thickening of the skin can contribute to the coarse facial appearance.  Patients also have musculoskeletal abnormalities including delayed shedding of primary teeth, pathologic fractures with minimal trauma, scoliosis, and joint hypermobility.  The facial and musculoskeletal abnormalities are typically not evident in early childhood.  Vascular anomalies have been described in patients including coronary and extracoronary arterial tortuosity, dilation, and aneurysms.  Patients appear to have an increased risk of Hodgkins and non-Hodgkins lymphoma.  

 

     Autosomal recessive HIES (DOCK8, Tyk2) patients have a clinical phenotype that differs from AD HIES.  These patients also develop recurrent skin/lung bacterial infections, mucocutaneous candidiasis, and severe atopic dermatitis but they also have an increased susceptibility to cutaneous viral infections (Mulloscum, Herpes simplex, Varicella, HPV).  Unlike AD HIES, patients with AR forms of disease do not form pneumatoceles following lung infections.  AR HIES patients also do not have recurrent pathological fractures or hyperextensibility.  Retained primary teeth has been reported in DOCK8 deficiency.

 

 

 

 

PATHOGENESIS

         

1.Autosomal Dominant Hyper IgE Syndrome  AD-HIES is caused by mutations in STAT3 (signal transducer and activator of transcription 3) which is involved in mediating cytokine signaling via the JAK-STAT pathway.  As a result, patients have defective Th17 differentiation of T-cells.  Th17 cells are believed to be important in the extracellular defense against bacteria and fungi.  Cytokines upregulated by IL-17 include the pro-inflammatory cytokines TNF alpha and IL-6 as well as the neutrophil chemotactic cytokine IL-8 and the neutrophil growth factor G-CSF and GM-CSF.  

 

2. Autosomal Recessive Hyper IgE Syndrome  -To date, 2 unrelated patients with Tyk2 deficiency have been reported.  Defects in Tyk2 also lead to impaired Th17 function.  Tyk2 is also involved in signaling for type I interferons (which explains the increased susceptibility to viral disease) and IL-12 (which explains the susceptibility mycobacteria and salmonella in one patient).  

 

      Recently described mutations in DOCK8 are likely to account for a greater proportion of AR HIES patients (almost 30 patients have been reported to date). The exact function of DOCK8 has not been elucidated at this time.  DOCK8 deficiency patients have additional immunologic abnormalities including decreased T-cell numbers and T-cell function.   

         

 

 

DIFFERENTIAL DIAGNOSIS

 

1. Wiskott-Aldrich Syndrome

2. IPEX syndrome

3. Omenn Syndrome (hypomorphic SCID)

4. Atypical Complete DiGeorge Syndrome

5. Netherton's Syndrome

 

                                 

EVALUATION

 

The diagnosis of HIES should be considered in patients with severe dermatitis starting during infancy, recurrent skin abscesses and pneumonia, and characteristic musculoskeletal abnormalities.  The presence of invasive infections helps to distinguish HIES from atopic dermatitis with elevated IgE.   The presence of cutaneous viral infections appears to be a key feature that  helps to distinguish DOCK8 deficiency from STAT3 deficiency.

 

STEP 1:  NIH Hyper IgE Scoring System (available in the resource section)

 

The use of this scoring system to quantify the above laboratory results and clinical findings is useful.
HIES is a multi-system disease with many features, one  of which is high IgE -  elevated IgE alone without significant infections or other somatic findings  will yield a very low predictive score.   

 

Classic AD-HIES patients often have scores above 40.  

 

AR-HIES patients will have a significantly lower score given the absence of pathologic fractures, scoliosis, hyperextensible joints, and pneumatocele formation. 

 

STEP 2:  Initial screening laboratory studies

 

-CBC with Differential
-Serum IgE levels
-IgG, IgM, IgA
-Specific antibody responses to vaccines
-Lymphocyte subset enumeration by flow cytometry
-Lymphocyte Mitogen proliferation
-Th17 Subset enumeration (this test is now commercially available) 
-Neutrophil chemotaxis assay (if available)

 

-Eosinophil counts are frequently elevated in HIES.  Eosinophilia is more severe in AR-HIES.  

 

-Serum IgE is often above 2,000 IU/ml and can be as high has 50,000 IU/ml.  However, some patients have been reported to have IgE levels below 1,000 IU/ml.

 

-Impaired specific antibody responses have been described in HIES.

 

-Decreased T-cell, B-cell, and NK-cell numbers have been described in AR HIES (DOCK8) patients.   These values are normal in STAT3 deficiency.

 

-Abnormal T-cell function has also been reported for DOCK8 deficiency (normal in STAT3 deficeincy).

 

-Low Th17 cell numbers are found in STAT3 and DOCK8 deficiency.   In one study, most patients with STAT3 deficiency had Th17 cell counts which were less than 0.2% of CD4 T cells (Shimke et al. 2010)

 

-Neutrophil chemotaxis assays are abnormal in a majority of patient with HIES.  


STEP 3:   Mutational Analysis

 

-STAT3 gene sequencing 
-DOCK8 gene sequencing
-Tyk2 gene sequencing

 

-STAT 3 testing is now commercially available (Gene Dx).

-DOCK8 and Tyk2 mutations is only available through specialized research centers.

 

 

 

                                                                   

MANAGEMENT

         

1.  Skin Care - Eczema should  be treated with emollients and topical anti-inflammatory medications.  Superinfection of eczema requires treatment with systemic antibiotics.  Bleach baths 3 times weekly can be helpful to decrease cutaneous Staphylococcus colonization.    

 

2.  Prophylactic Antibiotics -  Daily trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component twice daily) is useful to decrease skin and lung infections.   

 

3.  Prophylactic Antifungals  - Daily antifungal prophylaxis with an azole (fluconazole, itraconazole) may be useful for patients suffering from chronic mucocutaneous candidiasis (ex. Itraconazole 5mg/kg once daily).  

 

4.  Intravenous Immune Globulin (IVIG) therapy  - While patients do not typically have low serum IgG, some patients do have poor specific antibody responses and thus may benefit from IVIG replacement therapy if suffering from recurrent sinopulmonary infections.  Typical dosing is 400-600mg per kg administered once a month by IV or 100-150mg per kg once a week by subcutaneous infusion. 

 

5.  Interferon Gamma - There have been mixed results with use of interferon gamma in HIES patients.  Currently there is not enough evidence to utilize this therapy on a routine basis for HIES.  

 

6.  Interferon Alpha - There is a case report of this immunomodulator being used to treat severe cutaneous molluscum infection in HIES (see resource section).

 

 

                                                                           

RESOURCES

 

Diagnostic Resources   

 

1. Gene Dx STAT3 Sequencing

2. NIH Hyper IgE Scoring System

3. Th17 subset enumeration by flow cytometry

 

 

Literature Resources

 

1.  Holland 2007

     STAT3 mutations in Hyper IgE (NEJM)

 

2.  Holland 2008

     Hyper IgE Syndrome review

 

3.  Ochs 2009

     TH17 dysfunction and primary immunodeficiency

 

4.  Freeman 2006

     Pneumocystis infection in Hyper IgE

 

5.  Freeman 2007

     Fatal Pseudomonas and Aspergillus infections in Hyper IgE

 

6.  Kilic 2006

      Treatment of Molluscum in HIES with Interferon Alpha (case report)

 

7.  Orange 2010

     Use of cytokine therapy in primary immunodeficiency

 

8.  Su 2009

     DOCK8 combined immune deficiency (NEJM)

 

9.  Engelhardt 2009

     DOCK8 deficiency and aR Hyper IgE (JACI)

 

10.  Schimke 2010

        Immunologic and clinical findings to differentiate Hyper Ige Syndromes from atopic dermatitis