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Young girl with long-term rash, repeat staphylococcal infections
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A 7-year-old female with a history of eczema was admitted to the hospital for evaluation and treatment of a severe skin rash (Figure 1). She had a long history of this rash waxing and waning for years and was diagnosed by dermatology with severe atopic dermatitis and prescribed topical steroid cream, an emollient and ultraviolet B therapy. One year later, she was readmitted with another severe exacerbation of the rash (Figure 2). The rash responded to intensification of her topical treatment but was unrelenting, and with only her mother to help, who was “disabled” and wheelchair-bound, one can see how her dermatitis would frequently flair; never really clearing.
James H Brien
She was ultimately treated with systemic steroids and other immune modulators, such as cyclosporine. She actually had steroid-induced short stature diagnosed by an endocrinologist and received growth hormone therapy for a couple of years. It became apparent that she was having numerous episodes of Staphylococcus aureus infection, to include bacteremia and sepsis episodes, and at least one episode of pyomyositis of the right obturator muscle and early osteomyelitis of the right acetabulum (Figure 3). Her S. aureus skin abscesses and cellulitis episodes became more frequent; sparking an immune workup.
The patient had a long history of this rash and was admitted to the hospital for evaluation and treatment of a severe skin rash (Figure 1). One year later, she was readmitted with another severe exacerbation of the rash (Figure 2).
Source: Brien JH
She had numerous episodes of Staphylococcus aureus infection, and at least one episode of pyomyositis of the right obturator muscle and early osteomyelitis of the right acetabulum.
Her immunoglobulin G level was 1,120 mg/dL (reference range, 614-1,440); IgM level was 83 mg/dL (reference range, 48-333); IgA level was 214 mg/dL (reference range, 79-347); and her IgE level was 53,952 U/mL (reference range, 0-260). Her complement screen was normal, as were her cellular studies. Her response to various antigen challenges (vaccines) resulted in normal antibody responses. Six months later, her IgE level was repeated and found to be 103,682 U/mL. Her CBC differentials were usually normal, but occasionally revealed elevated eosinophil counts.
What’s Your Diagnosis?
A. Bruton syndrome
B. Job syndrome
C. Common variable immune deficiency
D. Severe atopic dermatitis
This patient turned out to have B: hyperimmunoglobulin E syndrome, historically known as Job syndrome. First described in 1966 by Davis and colleagues as Job syndrome because of its tendency to result in staphylococcal skin abscesses, similar to those described in the Book of Job in the Old Testament of the Christian Bible, this immune deficiency was eventually re-named hyper IgE syndrome, stemming from work done by Rebecca Buckley in 1972.
Since then, the syndrome has undergone further refinement to include dermatitis of varying severity, indistinguishable from severe AD, orthopedic abnormalities, sinopulmonary infections, mucocutaneous candidiasis and some characteristic facial features (frontal bossing, broad nasal alar base and coarse facial features). Eosinophilia is also a supportive feature, but the extremely high IgE level is the hallmark lab finding, which is usually more than 50,000 U/mL at the point of diagnosis. I would refer you to a review in Up To Date by Timothy La Pine and Harry Hill for an in-depth review of the chemistry and other details, including experimental therapies.
The last time I saw this patient was for a hospital follow-up visit, after yet another episode of S. aureus cellulitis of her right lower leg.
In 1952, Army Colonel Ogden Bruton reported a case of agammaglobulinemia in an 8-year-old male. As an X-linked disorder, it is therefore ruled out in this patient. It results in a mutation in Bruton’s tyrosine kinase (BTK) and failure of B-cell development. Although affected patients can have more frequent viral, fungal and parasitic infections, it is bacterial infections that cause severe, recurrent sinopulmonary disease, including otitis media, mastoiditis, meningitis, sepsis, etc, that are most problematic. These infections typically begin when the baby’s maternal IgG concentration drops below protective levels; usually by age 6 months. Diagnosis can be presumptive by obtaining a very low IgG level, as well as IgA and IgM. Also, inadequate antibody development to specific vaccine antigen is common. Confirmation is usually by detecting the mutation in the BTK gene in a specialty lab.
Management is by IgG replacement therapy, using intravenous immunoglobulin (IVIG) at 3- to 4-week intervals, to maintain trough IgG levels of about 500 mg/dL. Some older children and adolescents are using home-administered, subcutaneous IgG as an alternative to monthly IV therapy. Although it usually requires more frequent dosing, this method may be more cost-effective while being just as efficacious. It also frees the patient from having to maintain a port. Our immunologists are starting to use this technique in older children. Some clinics are using it in children as young as 2 years.
The last time I saw this patient was for a hospital follow-up visit, after yet another episode of S. aureus cellulitis of her right lower leg.
Common variable immunodeficiency, the most common primary immune deficiency, also has impaired immunoglobulin production; IgG (although not as severe as in Bruton syndrome), IgA and IgM. The clinical spectrum can be highly variable, ranging from minimal impact to those with severe, recurrent infections, autoimmune disease, inflammatory disease and lymphoid malignancies. The hallmark of therapy is also immunoglobulin replacement with IVIG, but the dose and interval is often significantly less compared with Bruton patients. An individual patient should have his dose titrated to his personal requirements. As with Bruton syndrome patients, older children and adults can also opt for periodic subcutaneous IgG.
As noted above, severe AD can be initially indistinguishable from hyper IgE syndrome. This patient has taught me to have a lower threshold for testing those with AD sooner than later. It should not take several years, resorting to systemic steroids and potent immunomodulation agents to trigger suspicion.
She was also noted to have a mild case of eczema herpeticum about the face and right ear (Figures 5 and 6).
The last time I saw this patient was for a hospital follow-up visit, after yet another episode of S. aureus cellulitis of her right lower leg (Figure 4), at which time she was also noted to have a mild case of eczema herpeticum about the face and right ear (Figures 5 and 6). Soon after that visit, she turned 18 years old and migrated to the adult service.
Columnist Comments
Most of these patients are followed by immunologists, infectious disease specialists or hematologists/oncologists, depending on availability, patient diagnosis and history, and availability of a clinic where IV infusions can be given, if needed. However, with proper motivation, the primary provider can manage these patients just as well if willing to stay abreast of changes in recommendations, which may require a significant time commitment.
For example, vaccine recommendations of these patients can be a fairly complicated but very important aspect of care. The AAP Red Book is a great source of vaccine information (section 1 and table 1.16), but still may require additional reading to know what to do with a particular patient. It might be best to have a team approach, with the primary provider co-managing these children with a subspecialist. However, the well-informed primary can do just as well or better, since they know the patient and their family better than anyone else. In any case, these children are doing much better nowadays than 34 years ago, when I was just out of residency. Many died or had severe morbidity (such as meningitis-associated deafness) due to the lack of proper care, availability of IVIG, better antimicrobials and improved immunizations. Hopefully, the next phase (after my time) will be curative measures.
For more information:
James H. Brien, DO, is vice chair for education in the department of pediatrics at McLane Children’s Hospital at Scott & White/Texas A & M College of Medicine in Temple, Texas. He is also a member of the Infectious Diseases in Children Editorial Board. Brien can be reached at: jhbrien@aol.com.
Disclosure: Brien reports no relevant financial disclosures.