AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Hyperimmunoglobulin E syndrome (HIES) was first described as Job syndrome in 1966, when 2 patients were reported with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints, and distinctive coarse faces.

Buckley et al expanded the clinical picture in 1972 and reported the association with elevated immunoglobulin E (IgE) in patients with HIES¹. HIES is now recognized as a primary immunodeficiency of unknown etiology characterized by recurrent skin abscesses, recurrent cystic lung disease, and elevated serum IgE levels. HIES was initially believed to have an autosomal dominant (AD) inheritance pattern, but sporadic cases of HIES and cases with autosomal recessive (AR) inheritance have been described.

In AD-HIES and sporadic cases, HIES is a part of syndrome that affects multiple organ systems, including the skeleton, connective tissue, and dentition systems. AD-HIES is inherited as a single-locus trait with various expressivity in some families with possible locus in chromosome arm 4q². In contrast, patients with AR-HIES lack skeletal or dental involvement and do not develop cystic lung disease. However, patients with AR-HIES are susceptible to viral infection characterized by severe Molluscum contagiosum and may develop severe neurological complications for unknown reasons³.

The immunologic features of HIES are characterized by recurrent skin abscesses, cystic lung infections (primarily Staphylococcus aureus and Candida species [chronic mucocutaneous candidiasis]), eczematous dermatitis, eosinophilia, and elevated IgE levels. Nonimmunologic features of AD-HIES include multiple bone fractures and other skeletal abnormalities, coarse facial features, joint hyperextensibility, and retained primary dentition. AR-HIES is distinguished from AD-HIES by increased susceptibility to viral infection as characterized by severe M contagiosum, lack of pneumatocele formation, and normal dentition and skeleton³. Sporadic cases of HIES were reported to have similar clinical features as those observed in AD-HIES⁴.

Patients with HIES appear to have an inadequate inflammatory response that may delay recognition of infections. Some investigators postulate that decreased neutrophil chemotaxis accounts for the poor inflammatory response; however, chemotactic aberrations are poorly reproducible among patients with HIES.

T-cell abnormalities, including a decrease in production of T_H1 cytokine and interferon-gamma (IFN-g) and an increase in production of T_H2 cytokine (IL-4), are variably present and would be consistent with elevated IgE levels. However, no direct association between IgE levels and an increase in IL-4 production has been reported. Identified cytokine abnormalities do not explain the high occurrence rate of bone fractures, osteoporosis, scoliosis, or the characteristic facies observed in patients with AD-HIES. Moreover, transgenic mice that lack IFN-g or overexpress IL-4 do not show characteristics of HIES.

Pathophysiology

Because recurrent skin and lung infections and marked elevation of IgE levels are the hallmarks of HIES, investigations have focused on defining a basic immune defect that leads to both recurrent infection with certain organisms (S aureus and Candida species) and elevated IgE synthesis in HIES. This line of research led to the findings of an imbalance of T_H1 and T_H2 responses, low IFN-g and relatively high IL-4 production and expression, defects in IFN-g and IL-12 pathway, underexpression of certain chemokines and adhesion molecules, and reduced expression of transforming growth factor b (TGF-b) and IFN-g mRNA in circulating activated (DR⁺) T cells^{5, 6}.

These findings may partly explain the marked elevation of IgE levels and recurrent infection in certain patients with microbesin HIES. However, serum IgE levels do not positively or negatively correlate with production or expression of these cytokines. IgE levels may also be associated with epigenetic regulation in patients with HIES. Some infants with HIES may not demonstrate elevated IgE levels from early infancy, while some older patients may demonstrate sudden decline in IgE levels without clinical improvement, as experienced by the author and other clinical immunologists.

More importantly, the above-referred immune abnormalities do not explain the facial, skeletal, joint, and dental defects in AD-HIES. Humans or mice lacking IFN-g production or the IFN-g receptor expression do not have facial or bony abnormalities. Patients with receptor defects of IFN-g or IL-12 have disseminated atypical mycobacterial infections with incomplete granuloma formation and do not exhibit clinical features of HIES⁷. Likewise, transgenic mice that overexpress IL-4 do not have the nonimmunologic features of HIES.

Recently, several researchers also explored possible defects in toll-like receptor (TLR)–mediated signaling in patients with HIES. However, the results do not indicate the defects in TLR responses or signaling, although a decrease in IFN-g production and a shift to predominant T_H2 responses were observed in these patients and were consistent with previous reports ^{8, 9}.

In addition to immune defects that affect IgE synthesis, defects of cell-mediated immunity have also been reported, consistent with decreased T_H1 responses. These include decreased or absent delayed-type hypersensitivity in some patients with HIES and decreased lymphoproliferative responses to S aureus, Candida species, and tetanus antigens. Decreased numbers and functions of CD8⁺ were also reported in some patients with HIES, but these findings vary in each patient. A decrease in T cells that express CD45RO, the marker for memory T cells, was also reported by other investigators.

Despite the rigorous efforts of investigators, genetic defects in HIES are still not identified. Patients with AR-HIES lack skeletal or dental abnormalities, but their clinical features are characterized by elevated IgE levels, eosinophilia, vasculitis, autoimmunity, CNS symptoms, and a high mortality rate, indicating a clinical entity distinct from AD-HIES. Identification of genetic defects in these two forms of HIES will be helpful and necessary to understand unique clinical features of HIES.

Recently, tyrosine kinase 2 (Tyk2) deficiency was identified in a patient diagnosed with HIES on the basis of clinical features¹⁰. In another patient with HIES, the presence of the IL-4-producing g/d T-cell clone was reported¹¹.

Frequency

United States

Frequency is undetermined. Published reports are from the United States and Europe.

International

Frequency is undetermined.

Mortality/Morbidity

Although the oldest reported patient was aged approximately 60 years, deaths in the second and third decades of life due to severe pulmonary disease and infection of pneumatoceles with Aspergillus species, Pseudomonas aerogunosa, or other organisms have been reported in patients with AD-HIES¹². Infections are the major cause of morbidity; approximately 80% of patients have pneumatoceles secondary to pneumonia, and a similar percentage have chronic mucocutaneous and ungual candidiasis. Morbidity includes bone fractures with minor injury in approximately 60% of patients with AD-HIES. In patients with AR-HIES, morbidity and mortality are closely associated with CNS complications and autoimmunity. Patients with AR-HIES seem to have frequent complications with varicella-zoster and herpes simplex viruses at a younger age. As described previously, patients with AR-HIES also frequently develop severe chronic refractory M contagiosum infections.

Race

HIES has been reported in all racial groups in the United States, but exact incidence cannot be determined because of the rarity of the disease. The presence of disease in multiple racial groups is significant because it suggests that multiple different mutations in the same genes are present.

Sex

Prevalence is equal in males and females. AD-HIES is inherited with variable penetrance.

Age

Patients with AD-HIES range in age from 0-60 years. Because not all patients have the same spectrum of infections, facial features, and skeletal anomalies, some patients are not identified until later in life when more chronic illness develops. Most patients with AR-HIES are diagnosed when younger than 20 years of age because of characteristic clinical features (eg, skin abscesses, recurrent pneumonia, markedly elevated IgE levels).

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Infants in families with hyperimmunoglobulinemia E syndrome (HIES) often exhibit severe eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas in the first few weeks of life. Lichenification quickly follows; then recurrent otitis media soon develops. Wheezing is not common; a persistent cough beginning in infancy is common. Chronic, disfiguring molluscum contagiosum infection has also been reported in patients with AR-HIES but not in those with AD-HIES.

Recurrent or chronic otitis media and sinusitis persist into adulthood. Although surgical intervention has been recommended in these patients, in the author's experience, sinus surgery seldom has favorable outcomes, and persistent otorrhagia may result after the surgery.

• Food and respiratory allergens can be identified using routine allergy testing; however, avoiding known allergens has minimal influence on patient's dermatitis or other atopic features of HIES.
• In patients with AD-HIES, fractures can result from minimal trauma (pathological fractures). Long bones, ribs, vertebrae, and pelvic bones are those most commonly broken.
• Pneumatoceles often develop occultly following pneumonia in people with AD-HIES. Chronic coughing with purulent sputum accompanies pneumatocele formation. In AR-HIES, pneumatoceles rarely develop.
• Isolated malignancies reported in people with HIES include lymphoma and squamous cell carcinoma.
• In a recent retrospective study, vasculitis was reported for 3 of 30 patients. Recurrent autoimmune hemolytic anemia was also reported in 2 of 13 patients with AR-HIES.
• In patients with AR-HIES, neurological symptoms are frequently seen, and these appear to be highly associated with vascular abnormalities including stenosis, occlusion, and aneurysm formation.
• Coronary artery aneurysms were reported in 2 patients with AD-HIES who were in their fifth decade of life. In contrast, fatal aneurysmal dilatation of the thoracic aorta has been reported in 2 adolescents with AR-HIES.
• Family members without HIES are not reported to have increased incidences of isolated fractures, facial anomalies, vasculitis, or malignancy. They also have normal IgE levels.
• When atopic predisposition is significant in the family, patients with HIES seem to have more severe skin and pulmonary symptoms.

Physical

Facial abnormalities and eczema somewhat varies at different ages. Infants and toddlers with AR-HIES often do not demonstrate the distinctive faces of older patients. By mid childhood, however, most patients have coarse faces, a prominent forehead, a broad nasal bridge, and a bulbous nose. Midline facial anomalies such as cleft lip and palatal abnormalities may be present. Craniosynostosis has been reported in a few patients. Such skeletal abnormalities do not appear to be present in patients with AR-HIES.

• Eczematous dermatitis and lichenification affect the face, trunk, and extremities in a distribution similar to that found in people without HIES who have atopic dermatitis. Dermatitis is pruritic, leading to excoriation. It differs from typical eczema in that the weeping, superinfected severe eczematous skin lesions are less frequent; patients with HIES instead develop boils, deep-seated cold abscesses, and even pyomyositis.
• In patients with AD-HIES, multiple fractures may lead to asymmetry in the extremities or the chest wall. Scoliosis developing during adolescence and vertebral abnormalities cause spinal deformity. One recent study reported hyperextensible joints in approximately 70% of patients. Dental abnormalities are also frequently seen in people with AD-HIES. Some patients with AD-HIES reportedly fail to shed their primary teeth. They may retain these teeth even as permanent teeth erupt.
• Chronic sinusitis, chronic bronchitis, and lung abscesses (for patients with AD-HIES) are common sinopulmonary findings. A purulent sputum-producing cough is common in patients who develop pneumatoceles, although some individuals have a dry cough associated with sinopulmonary infection. Wheezing is highly unusual in people with HIES and is more suggestive of atopy asthma with elevated IgE levels. The common manifestation in patients with AD-HIES includes a chronic cough and pneumatoceles in the second decade of life.

Causes

Linkage studies in some families suggest that mutations in a gene located on chromosome arm 4q cause AD-HIES, although the specific gene remains unidentified. Etiology is unknown for both AD-HIES and AR-HIES.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Atopic dermatitis is the primary alternative diagnosis. Atopic dermatitis is characterized clinically by a somewhat different appearance than the dermatitis in patients with HIES. Frequent weeping, superinfected lesions are seen in people with atopic dermatitis, whereas indurated boils and abscesses are seen in people with hyperimmunoglobulinemia E syndrome (HIES). Patients with atopic dermatitis also lack the distinctive facies and skeletal anomalies associated with AD-HIES. Patients with AD seldom have mucocutaneous candidiasis or treatment-resistant deep-seated sinopulmonary infection.

Other primary immunodeficiencies with eczematous dermatitis include Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Patients with these disorders tend to not have dermatitis as severe as that seen in people with HIES, and they lack the facial and skeletal abnormalities associated with AD-HIES. Patients with WAS have bleeding complications (eg, bloody diarrhea, CNS bleeding) secondary to thrombocytopenia and platelet dysfunction; platelet size is small in WAS. Patients with CGD do not develop pneumatoceles, although staphylococcal pneumonias are common, and their clinical features are characterized by granulomatous lesions involving multiple organs.

Omenn syndrome, a severe combined immunodeficiency disease (SCID) variant, is an AR disease with erythroderma resembling skin lesions of graft versus host disease, diarrhea, hepatosplenomegaly, hypereosinophilia, and markedly elevated serum IgE but low or absent other immunoglobulins. Omenn syndrome is associated with partial loss of functions of recombinase activity genes, RAG1 and RAG2. Absolute lymphocyte count is elevated because of activated oligoclonal and autoreactive T cells, but they are poorly responsive to mitogens or specific antigens; also, B cells are absent. This condition is fatal if not corrected with hematopoietic stem cell transplantation.

Common variable immunodeficiency disease (CVID) is often accompanied by eczema and other atopic features, but the eczema is usually milder than that seen in HIES, and the facial and skeletal anomalies are absent. In general, patients with CVID do not demonstrate elevated IgE levels. Staphylococcal keratoconjunctivitis is observed in both diseases.

IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) is characterized by early-onset insulin-dependent diabetes mellitus (DM), severe enteropathy (watery or bloody diarrhea, failure to thrive (FFT), extensive food allergy), and eczema/erythroderma/alopecia with elevated IgE levels. Autoimmune phenomena also often include thyroid grand, CNS, and hematological system. This is an X-linked recessive disorder associated with mutation of FOXP3, resulting in impaired development of CD4⁺CD25⁺ regulatory T cells in the thymus, which resulting in failure of peripheral tolerance. They are ill from early infancy.

The secondary immunodeficiency that may have features of HIES is human immunodeficiency virus (HIV) infection. Some patients with HIV develop extremely high IgE levels, show clinical signs and symptoms of allergy, and have high IL-4 production, but such clinical manifestation become less common after introduction of highly active anti-retroviral therapy (HAART).

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• An IgE level greater than 2 standard deviations higher than normal limits (often 100 times greater than the normal upper limits) is sufficient to confirm the diagnosis in a patient with characteristic clinical features. However, the clinician must be careful to exclude the severely atopic individual whose IgE may be elevated to similar levels. IgE levels may be deceptively low in an infant younger than 6 months and in older adults, whose IgE levels have been observed to decline.
• The CBC count typically reveals absolute eosinophilia with relatively normal neutrophil and lymphocyte counts.
• Immediate-type hypersensitivity skin tests for allergens can be positive for food and aeroallergens. Tests for detection of allergen-specific IgE may be less sensitive, more expensive, and often misleading in the presence of very high serum IgE levels; it may increase chances of false-positive results for allergen-specific IgE even with the use of the more specific enzyme-linked immunosorbent assay (ELISA).
• T-lymphocyte populations vary. Common abnormalities reported include a decrease in the CD8⁺ T cells and CD45RO⁺ memory T cells. Proliferative responses against mitogens (phytohemagglutinin, concanavalin A, and pokeweed) are typically normal. Delayed-type hypersensitivity skin test results are often negative in patients with hyperimmunoglobulinemia E syndrome (HIES) but are also negative in patients with severe atopic dermatitis. In patients with AR-HIES, decreased proliferative responses against specific antigens can be found.
• Neutrophil chemotaxis may be decreased in response to N-formyl-1-methionyl-l-leucyl-l-phenylalanine (FMLP), but the results are not necessarily reproducible, even in the same patient.

Imaging Studies

• CT of the lungs is required because almost 80% of patients with AD-HIES develop pneumatoceles that may become superinfected with organisms such as P aeruginosa and Aspergillus species. Pneumocystis jiroveci pneumonia has also been diagnosed in patients with AD-HIES. Bronchopulmonary fistulas should also be delineated. High-resolution CT is informative to evaluate pathological changes in the lungs.
• CT of the paranasal sinuses is indicated to evaluate for sinus disease.
• Fractures may be diagnosed by means of plain radiography.
• Technetium bone scanning and MRI may be needed to confirm the diagnosis and define the extent of osteomyelitis and deep-seated abscesses, respectively.

Other Tests

• Investigational studies have detected low IFN-g production by peripheral blood mononuclear cells (PBMCs) from 10 patients with AD-HIES in response to S aureus but not in response to Candida albicans or tetanus antigens. IL-12 supplemented to the culture promoted IFN-g production in the presence of these recall antigens in 10 controls but not in 10 AD-HIES patients. IL-12 is one of the key regulatory cytokines for IFN-g production, and these results may indicate dysregulated IFN-g and IL-12 axis in patients with AD-HIES. However, patients with defects of IFN-g and ILIL-12 axis do not reveal the similar clinical features of HIES.
• Impaired cell proliferative responses to specific antigens have been reported in patients with AR-HIES.
• Investigational studies have detected elevated quantities of IgE antibodies against S aureus and Candida species. IgE antibodies directed against tetanus and even HIV have also been detected. Impaired antibody responses to the phiX174 bacteriophage, the T-dependent tetanus protein antigen, and the T-independent pneumococcal polysaccharide antigen have been reported in some patients with AD-HIES. Secondary IgG antibody responses are most frequently impaired. However, antibody-forming capacities are heterogeneous in patients with HIES, and antibody deficiency cannot be solely attributable to infection susceptibility of these patients.
• Serum immunoglobulin D (IgD) levels are often elevated in patients with HIES, which is perhaps consistent with dysregulation of isotype switching because IgD is expressed on B cells prior to isotype switching to IgG or immunoglobulin A (IgA).

Procedures

• Bronchoscopy may be required in HIES to confirm the diagnosis of pulmonary infection.

Histologic Findings

Eosinophils are prominent in the skin, lung, and other localized inflammatory processes. Spleen and lymph nodes may show eosinophilic infiltrates. The thymus has appeared normal for age.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Prophylactic antimicrobials against S aureus and Candida species constitute the most important management of hyperimmunoglobulinemia E syndrome (HIES). The first-line anti-staphylococcal antibiotics are dicloxacillin or trimethoprim-sulfamethoxazole. Fluconazole is the drug of choice against Candida species.

• Eczematous dermatitis requires rigorous topical therapy with steroids and a moisturizing cream. Topical application of calcineurin inhibitors (tacrolimus and pimecrolimus) may also be used for controlling eczematous lesions, but their immunosuppressive actions on skin infection should be carefully monitored. A drug to control pruritus is often needed; this may be diphenhydramine or a longer-acting antihistamine such as loratadine, fexofenadine, desloratadine, or cetirizine. Dermatitis control becomes essential when casts are applied to manage fractures or scoliosis.
• When pneumonia develops, it is usually due to S aureus  infection. Generally, intravenous nafcillin or vancomycin for methicillin-resistant S aureus (MRSA) is first-line therapy. Haemophilus influenzae type b and non–typable strains also cause pneumonia; in these cases, cefuroxime intravenously is the drug of choice. Superinfection of pneumatoceles or lung abscesses with Aspergillus species requires intravenous amphotericin for several months; usually, surgical intervention is also necessary. When superinfection with P aeruginosa or other gram-negative bacteria is present, an aminoglycoside plus ceftazidime and surgical intervention are appropriate.
• In the case of P jiroveci pneumonia, intravenous trimethoprim-sulfamethoxazole is required. The author has seen unusually severe and prolonged pneumonitis from respiratory syncytial virus in infants; inpatient respiratory support has been required.
• Bone marrow transplantation is curative for a significant number of primary immunodeficiency diseases; however, one patient with HIES was reported to have recurrence of HIES following successful hematopoietic stem cell transplantation.

Surgical Care

• Thoracic surgical intervention to drain abscesses and empyemas, treat bronchial artery bleeding, and resect bronchopulmonary fistulas is frequently required. Lobectomy has been performed, although it can be technically difficult.
• Orthopedic procedures are needed to correct scoliosis or treat fractures.
• Surgical drainage of deep-seated abscesses in the skin and muscle may require postsurgical packing during a prolonged healing phase.

Consultations

• Dermatologic advice may be sought, but eczematous dermatitis often seems intractable.
• Pulmonologists may help optimize the management of chronic lung disease.
• Infectious-disease specialists may be helpful when difficult-to-treat organisms, such as MRSA, are suspected or isolated or when difficult-to-treat sites of infection are present. In general, prophylactic antibiotics covering S aureus and anticandidal drugs are helpful for patients with HIES.
• Orthopedic surgeons must consider the possibility of osteopenia contributing to delayed healing of fractures. They must also contend with the high risk of fracture-site infection, particularly with S aureus, related to pinning or to the overlying poorly controlled dermatitis. In addition, they need to manage significant scoliosis.
• In patients with AD-HIES with variable penetrance, input by a geneticist is necessary to help identify additional affected family members. More subtly affected individuals may be best diagnosed by a geneticist who is skilled in identifying the dysmorphic features of HIES.

Diet

A regular for age nutritious diet is needed. No therapeutic advantage has been observed with calcium or vitamin D supplementation for osteoporosis.

Activity

Encourage patients with HIES to exercise actively, attend school, and maintain employment. Discourage them from smoking, being exposed to smoke, and using illegal drugs because these actions further impair pulmonary function. Patients generally benefit from outdoor activities. Good skin care is essential. Given the reasonably good survival rate into adulthood, healthy activities can help patients not to be emotionally crippled from this immunodeficiency disease.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Patients with severe hyperimmunoglobulinemia E syndrome (HIES) require prophylactic antibiotics to cover S aureus and an antifungal to cover C albicans. Pneumonia and deep-seated abscesses caused by S aureus are treated intravenously with nafcillin if the isolate is methicillin-sensitive and with vancomycin if it is methicillin-resistant. Lung abscesses superinfected with Aspergillus species require intravenous amphotericin B for several months. Gram-negative bacteria, including P aeruginosa, require an aminoglycoside and a third-generation cephalosporin or another synergistic antibiotic.

Any deep-seated abscess must be adequately debrided and drained surgically.

Eczematous dermatitis is treated with a topical a topical corticosteroid, a moisturizing cream, and an antihistamine to decrease pruritus.

Respiratory care may require a beta2-agonist and an inhaled corticosteroid with careful monitoring of pulmonary function tests and clinical response.

Drug Category: Antibiotics

Antibiotics are first line therapy for S aureus. Response can often be achieved using oral dicloxacillin when the organism is methicillin-sensitive S aureus (MSSA). For more deep-seated infections, intravenous therapy with nafcillin or oxacillin is necessary. MRSA infections are usually managed with intravenous vancomycin because these organisms are often hospital acquired. Community-acquired MRSA infections at more superficial, cutaneous sites may be susceptible to oral fluoroquinolones, clindamycin, or trimethoprim-sulfamethoxazole. Vancomycin resistance (ie, glycopeptide intermediate S aureus resistance [GISA]) is managed with antibiotics such as quinupristin-dalfopristin (Synercid), linezolid, or fluoroquinolones. For severe staphylococcal infections, a combination of a beta-lactam antibiotic and an aminoglycoside may be the initial treatment.

Additional antistaphylococcal therapy may include topical mupirocin to the nares to eradicate colonization.

Drug Category: Topical corticosteroids

Multiple preparations of topical corticosteroids of varying potencies are available. The eczematous dermatitis of HIES typically requires high-potency ointments used in conjunction with an emollient bid. Dermatitis may subside for no apparent reason; interestingly, it may improve during acute infection.

Adverse effects that must be discussed with the patient and family include damage to the skin, especially of the face and intertriginous areas, and the potential for systemic absorption leading to growth impairment, adrenal suppression, and the other common complications of systemic steroids. Occlusive dressings increase systemic absorption from the skin.

Drug Category: Topical calcineurin inhibitors

These agents modify immune processes that promote inflammation.

Drug Category: Second-line antistaphylococcal antibiotics

In specific cases in which the patient has hypersensitivity to penicillin and a limited cutaneous infection with S aureus or if the patient has a more minor infection such as otitis media, trimethoprim-sulfamethoxazole or cephalexin can be considered for management. MSSA infection may be sensitive to cephalexin. Certain community-acquired MRSA infections may be sensitive to trimethoprim-sulfamethoxazole.

Drug Category: Antifungal agents

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Pneumonia in patients with hyperimmunoglobulinemia E syndrome (HIES) may be extremely complicated and require prolonged inpatient management. The abnormal inflammatory response with progression to pneumatoceles requires close observation and possible surgical intervention. Empyemas, bronchopleural fistulas, and hemoptysis caused by erosion into bronchial arteries are potential emergencies.
• Other infections requiring inpatient care include osteomyelitis, which may be difficult to distinguish clinically from fractures, and deep-seated abscesses or myositis requiring incision, drainage, and packing.
• When vigorous antibiotic therapy is required for infection, fungal prophylaxis is also required because most patients are at increased risk for mucocutaneous and invasive fungal infections, predominantly Candida and Aspergillus. Pay careful attention to signs of superinfection of lung abscesses with Aspergillus.

Further Outpatient Care

• Dental care must be provided when primary teeth fail to be shed and interfere with eruption of permanent teeth in AD-HIES patients.

In/Out Patient Meds

• See Medical Care.

Transfer

• Most clinical immunologists feel strongly that the great complexity of medical problems for any primary immunodeficiency disease requires treatment of those patients by an immunologist. Subtle signs of infection, complex clinical features, and high complication rates in patients with HIES suggest a vital role for a clinical immunologist for the care of HIES patients.
• A major reason for transfer is for thoracic surgery management of a lung abscess, bronchopulmonary fistula, or erosion of infection into a bronchial artery.

Deterrence/Prevention

• Prophylactic oral antibiotic coverage for S aureus and an antifungal agent against Candida species are required for most patients.
• Prenatal diagnosis is currently not available; it awaits identification of the gene responsible for HIES, which is possibly located on chromosome arm 4q in patients with AD-HIES.

Complications

• Pulmonary complications of infection, such as bronchopulmonary fistula or bleeding, are surgical emergencies.
• Craniosynostosis has been reported in several patients with AD-HIES.
• Occasional cases of malignancy have been reported. These reports are so infrequent that an increased risk for malignancy is difficult to define. Nevertheless, increased malignancies are common in primary immunodeficiency diseases.
• In 13 patients with AR-HIES, 5 were reported to have CNS symptoms associated with vascular anomalies (stenosis, occlusion, and aneurysm formation), and 3 of 5 these patients died with subsequent complications (cerebral infarction and subarachnoid hemorrhages).
• Recently, fatal aneurysmal dilatation of the thoracic aorta was reported in 2 adolescents with AR-HIES. Coronary artery aneurysms were also reported in 2 patients with AD-HIES patients who were in their fifth decade of life when aneurysms were diagnosed.

Prognosis

• Follow-up care for patients with HIES is poorly documented, but it is believed most patients with AD-HIES survive into mid adulthood. Chronic pulmonary disease compromises function and affects the mortality rate. Most deaths in the second to third decade of life result from lung abscesses superinfected with Aspergillus species or gram-negative bacteria. More aggressive medical and surgical care may decrease this mortality rate.
• Failure of hematopoietic stem cell transplantation to correct HIES in one patient raises the question of whether therapy for HIES with any form of stem-cell reconstitution would be effective.

Patient Education

• Patients and their families must be alert to early subtle signs of infection and seek appropriate medical care. In the author's experience, primary care physicians and surgeons also often underestimate the extent of deep abscess formation and need for surgical drainage.
• Daily care for eczema is tedious. Persuading patients and their families of the utility of daily care is difficult when dermatitis does not respond uniformly to medical management.
• The Immune Deficiency Foundation is an important resource for education and for support for patients and families with any primary immunodeficiency disease. The foundation's address is 40 W Chesapeake Ave, Suite 308, Towson, MD 21204; some states have local chapters. The telephone number for consultation calls is (800) 296-4433.
• The Jeffrey Modell Foundation at 747 3rd Avenue, New York City, NY 10017 also provides support and patient education. The telephone number is (212) 819-0200.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Eczema.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to adequately estimate the extent of localized infection requiring drainage is the most common medical liability for hyperimmunoglobulinemia E syndrome (HIES).
• Failure to differentiate between HIES and severe atopic dermatitis is a potential legal risk because antimicrobial prophylaxis is an integral part of managing HIES and is not appropriate for uncomplicated atopic dermatitis.

Special Concerns

• Invasive pulmonary Aspergillus species and, occasionally, visceral infection with candidal species may occur. P jirovesii pneumonia is rare but can occur in patients with HIES.
• Zoonotic infections have not been reported, and the risk is probably not increased because splenic dysfunction is not a component of HIES.
• Pregnant women with HIES have a high risk of pneumonia complicated by chronic pulmonary infection. Difficulty breathing is also a risk.
• AR-HIES patients may be at risk for neurological complications

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Chest radiograph of a patient with autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES) and a lung abscess following multiple staphylococcal pneumonias. Aspergillus fumigatus was isolated from the abscess.
	View Full Size Image
Media type:  X-RAY

Media file 2:  Father and daughter with autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.
	View Full Size Image
Media type:  Photo

Media file 3:  Mother and son with autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

1. Buckley RH. Disorders of the IgE system. In: Steigm ER, ed. Immunologic Disorders in Infants and Children. 4^th ed. 1996:413-422.
2. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. Mar 4 1999;340(9):692-702. [Medline].
3. Renner ED, Pawlita I, Hoffmann F, et al. No indication for a defect in toll-like receptor signaling in patients with hyper-IgE syndrome. J Clin Immunol. Jul 2005;25(4):321-8. [Medline].
4. Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. Sep 1999;65(3):735-44. [Medline].
5. Borges WG, Augustine NH, Hill HR. Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome. J Pediatr.