Hyperimmunoglobulinemia E (Job) Syndrome 

Updated: Oct 21, 2015
Author: Harumi Jyonouchi, MD; Chief Editor: Russell W Steele, MD 

Overview

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/recurrent bone fractures, and distinctive coarse faces.[1] See the images below.

Father and daughter with autosomal dominant (AD) h Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.
Mother and son with autosomal dominant (AD) hyperi Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (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.

Buckley et al expanded the clinical picture in 1972 and reported the association with elevated immunoglobulin E (IgE) in patients with hyperimmunoglobulin E syndrome.[2] Hyperimmunoglobulin E syndrome is now recognized as a primary immunodeficiency disease characterized by recurrent skin abscesses, recurrent pneumonica with pneumotocele, eczematous dermatitis, and elevated serum IgE levels. HIES was initially reported to have an autosomal dominant (AD) inheritance pattern, but cases with autosomal recessive (AR) inheritance and sporadic cases have been reported.

Mutations of the signal transducer and activator of transcription 3 (STAT3) gene were shown to cause the AD HIES by 2 groups independently.[3, 4] In addition, tyrosine kinase 2 deficiency (tyk2) deficiency was reported in 2 patients with HIES, but tyk2 deficiency is also characterized by severe viral and bacterial infections.[5, 6] A fair numbers of patients with AD HIES have STAT3 mutations (around 70%); however, some patients have AD HIES-like disease without STAT3 mutations.

In AD HIES and sporadic cases, HIES manifests as a disease that affects multiple organ systems, including the skeleton, connective tissue, and dentition. AD HIES is inherited as a single-locus trait with various expressivity in some families. 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 reasons.[7] Some patients with AR HIES have mutations in DOCK8.[8] Subsequent studies in animals and affected humans revealed an important role in DOCK8 in T and B cell development and functions; DOCK8 deficiency is now known to cause a combined immunodeficiency rendering the affected patients susceptible to viral, fungal, and bacterial infections.[9]

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 TH 1 and TH 2 responses, decreased production/expression of interferon (IFN)-γ in contrast to relatively elevated production/expression of interleukin (IL)-4, defects in IFN-γ and IL-12 pathways, underexpression of certain chemokines and adhesion molecules, and reduced expression of transforming growth factor β (TGF-β) and IFN-γ messenger RNA (mRNA) in circulating activated (DR+) T cells.[10, 11] However, serum IgE levels do not positively or negatively correlate with production or expression of these cytokines.

More important, the above-referred immune abnormalities do not explain the facial, skeletal, joint, and dental defects in AD HIES. Patients with receptor defects of IFN-γ or IL-12 have disseminated atypical mycobacterial infections with incomplete granuloma formation and do not exhibit clinical features of HIES.[12] Studies in toll-like receptor (TLR)–mediated signaling in patients with HIES did not reveal anty abnormalities either.[13, 14]

In addition to immune defects that affect IgE synthesis, defects of cell-mediated immunity have also been reported, consistent with decreased TH 1 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. A decrease in T cells that express CD45RO, the marker for memory T cells, was also reported by other investigators. In one patient with HIES, the presence of the IL-4-producing γ/δ T-cell clone was reported.[15]

Puzzling clinical features of AD HIES became better understood following identification of STAT3 mutations as a cause of AD HIES. The initial report of the STAT3 mutation in patients with HIES described dominant-negative mutations in the DNA binding domain of STAT3.[3] A subsequent study reported 2 hot spots of mutations: DNA binding and SH2 domains.[4] Other mutations of STAT3 in AD HIES have also been described.[16]

STAT3 is implicated in the signal transduction of multiple cytokine families including the IL-2/common g chain family (IL-2, IL-7, IL-9, IL-15, IL-21), the IL-6/gp130 family (IL-6, IL-11, IL-27, IL-31, ciliary neurotropic factor, oncostatin M, leukemia inhibitory factor), IFNs, and the IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26). STAT3 is also implicated in signaling pathways of IL-12, IL-23, Flt3 ligand, macrophage-colony stimulating factor (M-CSF), granulocyte-colony stimulating factor (G-CSF), leptin, and growth hormone.[17] STAT3 mutations have a key role in the signaling pathways of multiple cytokines and affect multiple organ systems, as revealed in humans and STAT3 knockout (KO) mice. Impaired STAT3 signaling is implicated with the following abnormalities[18] as described below:

  • CD4+ T cells: Impaired STAT3 signaling causes deficiency of Th17 cells and impaired IL-10 production.[19] Th17 cells are aTh-cell subset characterized by the production of IL-17A, IL-17F, IL-21, IL-22, IL-26, and CCL20. They play a major immune defense against extracellular pathogens such as mycobacterium and fungi. Patients with AD HIEA are shown to have impaired Th17 cell differentiation.[20, 16] This is attributed to impaired STAT3 mediated signaling of IL-6, a key differentiation factor for Th17 cells. STAT3 deficiency abrogates the ability of IL-6 and IL-27 to induce production of IL-10 by CD4+ T cells, resulting in impaired IL-10 production.

  • B cells: In STAT3 KO mice, these mice are found to have impaired antibody (Ab) production against T-dependent antigens (TD-Ags). Patients with AD HIEA are also reported to have impaired production of functional Abs. However, reduced numbers of isotype-switched memory B cells in patients with AD HIES are reported to be not associated with their functional Ab production or infection history.[21]

  • Myeloid cells: Patients with AD HIES have up-regulated proinflammatory cytokine production. One of the counter-regulatory measures for proinflammatory cytokines is autocrine production of IL-10 by myeloid lineage cells such as macrophages and monocytes. Because IL-10 receptor signaling is mediated by STAT3, this IL-10 mediated suppression is lost in STAT3 KO mice as well as in patients with AD HIES who have STAT3 mutations. This defect likely explains hyperinflammatory features of AD HIES. Impaired signaling via Flt3 ligand also affects dendritic cell (DC) development and results in lower numbers of DCs in STAT3 KO mice.[17]

  • Osteoclasts: Cytokines of IL-6 family have roles in bone homeostasis and their signaling pathways mediates via STAT3. Thus, impaired STAT signaling results in increased bone resorption by osteoclasts. This may explain why AD HIES affect the skeletal system.

The discovery of the dedicator of cytokinesis 8 (DOCK8) mutation as a cause of AR HIES was also helpful to understand clinical features of AR HIES with this mutation.[8, 22] AR-HIE syndrome is distinguished by recurrent sinopulmonary infection, severe cutaneous viral infection often caused by HSV, HPV, HZV, and molluscum contagiosum virus in addition to elevated IgE and lack features involving the skeletal system. These patients are also known to be at high risk of malignancies including squamous cell carcinoma, cutaneous T cell lymphoma/leukemia, and Burkitt lymphoma in late childhoold and early adulthood.[23] Recent studies also revealed that DOCK8 serves as an adaptor that links TLR9-MyD88 signaling to B-cell activation.[24] This may partly explain Ab deficiency observed in DOCK8 deficiency. Recent studies of 25 patients with AR HIES at one center also report a high frequency of hepatic disorders.[25]

These patients are also characterized by CNS symptoms caused by CNS vasculitis and infection including JC virus associated progressive multifocal leukoencephalopathy. DOCK8 belongs to the DOCK180 superfamily of proteins which have a role in guanine nucleotide exchange for Rho family GTPases. DOCK180- related guanine nucleotide exchange factors are shown to have roles in actin cytoskeletal rearrangement, cell migration, integrin mediated cell adhesion, phagocytosis, cell fusion, cell polarization, and synapse formation. Patients with AR HIES were also shown to have impaired Th17 cell development.[26]

It should also be noted that patients with AR HIES have low T-cell excision circles (TRECs), indicating that these patients may be detected by severe combined immunodeficiency (SCID) newborn screening with low, but not absent, TREC copies.[27]

Epidemiology

Frequency

United States

Frequency is undetermined. Published reports are from the United States and Europe. A recent population-based study concluded that the incidence of all primary immunodeficiencies markedly increased between 1976-2006.[28]

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 aeroginosa, or other organisms have been reported in patients with AD HIES.[29] 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[30] , autoimmunity, and malignancy. Patients with AR HIES with DOCK8 mutations are known to have frequent complications with cutaneous viral infections caused by varicella-zoster, herpes simplex viruses, HPV, and molluscum contagiosum virus at a younger age. Patients with AR HIES are also know to develop severe chronic refractory molluscum contagiosum at high frequency. DOCK8 mutation is now considered to cause combined immunodeficiency affecting T and B cell numbers and functions profoundly, resembling an SCID variant.

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 and AR HIES is inherited with variable penetrance.

Age

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

 

Presentation

History

Infants in families with HIE syndrome 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 M 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 HIE syndrome.

  • In patients with AD HIE syndrome, fractures can result from minimal trauma (pathological fractures). Long bones, ribs, vertebrae, and pelvic bones are those most commonly affected.

  • Pneumatoceles often develop occultly following pneumonia in people with AD HIE syndrome. Chronic coughing with purulent sputum accompanies pneumatocele formation. In AR HIE syndrome, pneumatoceles rarely develop.

  • Susceptibility to malignancies, including squamous cell carcinoma, cutaneous T-cell lymphoma/leukemia, and Burkitt lymphoma, was reported in patients with AR HIES.[23] DOCK8 mutation is a known cause of AR HIES and has a role in T-cell development and function, which helps explain these clinical features.

  • 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. Etiology of vascular abnormalities are implicated with CNS vasculitis and infection.

  • 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.

  • Patients with tyk2 deficiency exhibit more severe clinical features characterized by extreme vulnerability to intracellular bacteria as well as extracellular bacteria. This is attributed to impaired signaling mediated by interleukin (IL)-6, IL-10, IL-12, and IL-23.[5]

Physical

Facial abnormalities and eczema varies with age. Infants and toddlers with AD HIES often do not demonstrate the distinctive facial features found in older patients with AD HIES. By mid childhood, however, most patients with AD HIES 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 HIE syndrome 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. Multiple guidelines have been established for the diagnosis and management of atopic dermatitis.[31, 32]

In patients with AD HIES fractures may lead to asymmetry in the extremities or the chest wall. Scoliosis develops during adolescence and vertebral abnormalities cause spinal deformity. One recent study reported hyperextensible joints in approximately 70% of AD HIES 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.

Because HIES affects multiple organ systems and clinical features may change with age, the National Institutes of Health (NIH) developed a scoring system for clinical diagnosis for HIES. A clinical point score of more than 40 is reported to be highly likely to have AD HIES.[26] Clinical findings listed in this scoring system include highest serum IgE level, skin abscesses, pneumonia, parenchymal lung anomalies, retained primary teeth, scoliosis (maximum curvature), fractures with minor trauma, highest eosinophil count, characteristic coarse facial features, midline anomaly, newborn rash, eczema (worst stage), frequency of upper respiratory tract infection, candidiasis, other serious infections, fetal infection, hyperextensibility, lymphoma, increased nasal width, and high palate. Scores are corrected with young age.

Causes

As detailed in Pathophysiology, recent studies revealed that many cases of AD HIES are associated with STAT3 mutations and most AR HIES associated with DOCK8 mutations.

 

DDx

Diagnostic Considerations

Atopic dermatitis is the primary alternative diagnosis. Atopic dermatitis is clinically characterized by a somewhat different appearance than the dermatitis in patients with HIES. Frequent weeping, superinfected lesions are seen in patients with atopic dermatitis, whereas indurated boils and abscesses are seen in HIES subjects.

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 HIES patients and 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 (OS), a severe combined immunodeficiency disease (SCID) variant, is a syndrome caused by hypomorphic mutations of multiple genes associated with SCID. Erythroderma presents in OS is essentially the same as seen in graft versus host disease and their clinical features are also characterized by diarrhea, hepatosplenomegaly, hypereosinophilia, and markedly elevated serum IgE levels but low or absent other Ig isotypes.

Hypomorphic mutations of genes associated with OS include those causing SCID with RAG1 and RAG2 hypomorphic mutations being the most common. 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 treated 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.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome is characterized by early-onset insulin-dependent diabetes mellitus (IDDM), severe enteropathy (watery or bloody diarrhea, failure to thrive [FTT], extensive food allergy), and eczema/erythroderma/alopecia with elevated IgE levels. Autoimmune phenomena also 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 result in impaired peripheral tolerance. IPEX patients are ill from early infancy. Primary immune deficiencies with aberrant IgE production were reviewed by Ozcan et al.[33]

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).

Differential Diagnoses

 

Workup

Laboratory Studies

A maximum IgE greater than 10 standard deviations higher than age-appropriate normal limits (often 100 times greater than the normal upper limits) is sufficient to confirm the diagnosis of AD HIES 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 elevated absolute eosinophilia with relatively normal neutrophil and lymphocyte counts.

Immediate-type hypersensitivity skin test results for allergens can be positive for food and aeroallergens, but severe eczematous skin can cause false-positive results. 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 in AD HIES. Delayed-type hypersensitivity skin test results are often negative in patients with 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.

Absence or significant decrease in the number of Th17 cells identified using intracellular staining of interleukin (IL)-17 is characteristic in patients with AD HIES caused by STAT3 mutations, as well AR HIES with DOCK8 deficiency.[20, 22, 26] Enumeration of Th17 cell by flow cytometry is commercially availabe at Children's Hospital and Health System, Medical School of Wisconsin, as well as several triage centers.

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.

TREC is reported to be low in AR-HIES patients with DOCK8 mutation.[27]

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.

Imaging studies of CNS may also be indicated in patients with AR HIES who reveal CNS symptoms.

Other Tests

Investigational studies have detected low IFN-γ 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-γ production in the presence of these recall antigens in 10 controls but not in 10 patients with AD HIES. IL-12 is one of the key regulatory cytokines for IFN-γ production, and these results may indicate dysregulated IFN-γ and IL-12 axis in patients with AD HIES. This is attributed to impaired STAT3 signaling that partly mediates by signaling via receptors of IL-12 and IL-23. In tyk2 deficiency, production of IFN-γ and type 1 IFN is profoundly impaired.

Impaired cell proliferative responses to specific antigens have been reported in patients with AR HIES. This is likely associated with a role of DOCK8 in T- and B-cell functions.[9]

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. Impaired IgG antibody production against T-dependent Ag in patients with AD HIES may be attributed to impaired STAT signaling via IL-6 and IL-21 because these cytokines have crucial roles in B-cell differentiation.

Serum IgD levels are often elevated in patients with HIES, which is perhaps consistent with dysregulation of isotype switching: IgD is expressed on B cells prior to isotype switching to IgG or IgA.

Th17 cells play a crucial role in immune defense against fungi and mycobacterium, triggering neutrophilic chemotaxis and subsequent neutrophilic inflammation. Th17 cell differentiation largely depends on microenviromental concentrations of IL-6, IL-1ß, and TGF-ß. STAT3 mutations impairs IL-6–mediated signaling, resulting in greatly diminished numbers of Th17 cells. This is more strikingly shown in near absence of Candida -specific memory Th17 cells in patients with AD HIES who have STAT mutations.[20]

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

Medical Care

Prophylactic antimicrobials against S aureus and Candida species constitute the most important management of 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.

Chest radiograph of a patient with autosomal domin Chest radiograph of a patient with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES) and a lung abscess following multiple staphylococcal pneumonias. Aspergillus fumigatus was isolated from the abscess.

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 (BMT) 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. Given a role of DOCK8 in T- and B-cell development/function, DOCK8 deficiency may require BMT at an earlier age, depending on penetrance.

Guidelines for the diagnosis and management of primary immunodeficiencies have been established.[34]

Surgical Care

See the list below:

  • 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

See the list below:

  • 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 AD HIES. Likewise, genetic counseling may also be indicated for patients with AR HIES who have DOCK8 deficiency with high risk of malignacies and neurological manifestations.

Diet

A regular-for-age nutritious diet is needed. No therapeutic advantage has been observed with calcium or vitamin D supplementation for osteoporosis. Even if the patient reveals positive reactivity in prick skin testing or in food allergen–specific IgE, avoidance of food allergens seldom attenuates eczema skin lesions.

Activity

See the list below:

  • Encourage patients with hyperimmunoglobulinemia E syndrome 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

Medication Summary

Patients with severe HIES require prophylactic antibiotics to cover S aureus and an antifungal to cover C albicans. Pneumonia and deep-seeded 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-seeded abscess must be adequately debrided and drained surgically.

Eczematous dermatitis is treated with 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.

HIES patients who were found to have profound functional Ab deficiency may be benefited from exogenous immunoglobulins given monthly basis. However, in most patients with AD HIES, Ab deficiency or decreased memory B cell numbers are not associated with infection history.[21]

Antibiotics

Class Summary

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 methicillin-resistant S aureus (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.

Dicloxacillin

Well-absorbed but poor aftertaste. Follow by 1 tsp chocolate syrup to increase palatability. Binds to ≥ 1 penicillin-binding protein, which, in turn, inhibits synthesis of bacterial cell walls.

Nafcillin

Use for invasive infections including abscesses. Vancomycin preferred for CNS infection because does not penetrate well into CSF.

Vancomycin (Vancocin, Vancoled)

Use for MRSA infection and penicillin allergy. Monitoring of peak and trough levels is controversial; steady state is achieved at peak 60 min after the third through fifth consecutive dose. Achieving above MIC for infecting organism is critical; consultation with infectious disease specialist may be appropriate, particularly with advent of GISA.

Linezolid (Zyvox)

May be considered for therapy for MRSA, GISA, vancomycin-resistant enterococci, and penicillin-resistant pneumococci but does not cover gram-negative bacteria.

Has good PO absorption. Available as PO susp at 100 mg/5 mL.

Quinupristin/Dalfopristin (Synercid)

Active against MRSA, MSSA, penicillin-sensitive or resistant S pneumoniae, and vancomycin-resistant Enterococcus faecium. Administered IV only. Inhibits CYP3A4.

Mupirocin (Bactroban)

Topical antibiotic used to eliminate S aureus colonization, particularly of the nares.

Topical corticosteroids

Class Summary

Multiple preparations of topical corticosteroids of varying potencies are available. The eczematous dermatitis of hyperimmunoglobulinemia E syndrome 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.

Triamcinolone topical (Aristocort)

Categorized in group III potency with betamethasone dipropionate lotion 0.05%. Treats inflammatory dermatosis that is responsive to steroids. Decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Betamethasone dipropionate ointment 0.05% (Alphatrex, Diprolene, Maxivate)

Categorized as group II, more potent than group III topical steroids. For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Topical calcineurin inhibitors

Class Summary

These agents modify immune processes that promote inflammation.

Tacrolimus, topical 0.03%, 0.1% (Protopic)

Reduces itching and inflammation by suppressing the release of cytokines from T cells. Also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in the early stages of T-cell activation. Additionally, may inhibit release of preformed mediators from skin mast cells and basophils, and may down-regulate expression of FCeRI on Langerhans cells. Indicated for eczema and atopic dermatitis only after other treatment options have failed.

Pimecrolimus (Elidel cream)

Indicated for eczema and atopic dermatitis. Indicated only after other treatment options have failed. First nonsteroid cream approved in the United States for mild-to-moderate atopic dermatitis. Derived from ascomycin, a natural substance produced by fungus Streptomyces hygroscopicus var ascomyceticus. Selectively inhibits production and release of inflammatory cytokines from activated T cells by binding to cytosolic immunophilin receptor macrophilin-12. Resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release.

Cutaneous atrophy was not observed in clinical trials, a potential advantage over topical corticosteroids.

Second-line antistaphylococcal antibiotics

Class Summary

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.

Trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)

Second line because it achieves significant intracellular levels.

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Cephalexin (Keflex, Biocef, Keftab)

Can be used in penicillin-allergic patients, but its tissue penetration is less reliable than TMP-SMZ.

First-generation cephalosporin arrests bacterial growth by inhibiting bacterial cell wall synthesis.

Antifungal agents

Class Summary

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.

Fluconazole (Diflucan)

DOC to prevent or treat candidal infections.

Fungistatic activity.

Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Amphotericin B (Amphocin, Fungizone)

First-line therapy for Aspergillus, Candida resistant to fluconazole, and other invasive fungi.

 

Follow-up

Further Outpatient Care

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

There is on case report of the use of IFN-α for treatment of severe molluscum skin infection in one patient with HIES.[35]

Further Inpatient Care

See the list below:

  • Pneumonia in patients with 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.

  • In patients with AR HIES, cutaneous viral infection can be very treatment-resistant and a prolonged treatment may be required.

Inpatient & Outpatient Medications

See the list below:

  • See Medical Care.

Transfer

See the list below:

  • 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 patients with HIES.

  • 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

See the list below:

  • Prophylactic oral antibiotic coverage for S aureus and an antifungal agent against Candida species are required for most patients.

  • Prenatal diagnosis may be possible in a child born to parents with know mutations with STAT3 or DOCK8.

Complications

See the list below:

  • 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 mainly in AR-HIES patients, mainly originating from skin. Careful monitoring is indicates.

  • 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 who were in their fifth decade of life when aneurysms were diagnosed.

Prognosis

Follow-up care for patients with HIES is not well documented, but 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. This may also be associated with mutations causing HIES. Patients with DOCK8 deficiency may be expected to benefit from stem-cell reconstitution more so than other HIES patients.

Patient Education

See the list below:

  • 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 use 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 eMedicineHealth's Skin Conditions and Beauty Center. Also, see eMedicineHealth's patient education article Eczema.