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.
Diagnosis of gene mutations is based on whole exome sequencing (WES) studies, but some mutations may not be detected by WES and additional studies may be required.
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.
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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.
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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.
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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.
