Job Syndrome


INTRODUCTION


Background
First described in 1966, the hyperimmunoglobulin E (hyper-IgE or HIE) syndrome is a rare immunodeficiency disorder that has an autosomal dominant inheritance pattern. HIE has variable expressivity and is associated with multiple abnormalities. The most common findings are recurrent skin abscesses (hence, the name Job syndrome), pneumonia with pneumatocele development, and high serum levels of IgE. Facial, dental, and skeletal features are also associated with this syndrome.
Although most cases are sporadic, multiplex families displaying autosomal dominant and autosomal recessive inheritance have been described.1 Autosomal recessive patients tend to have severe molluscum contagiosum and other viral infections and may develop severe neurological complications. These patients also lack skeletal or dental involvement and do not develop lung cysts. Some authorities believe 2 separate syndromes exist, not one.
Pathophysiology
The pathophysiology of Job syndrome is not completely understood. Patients consistently have a poor, delayed hypersensitivity response to antigens. This delayed response is associated with alterations in T-lymphocyte populations and various interleukin and cytokine abnormalities. One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils. This defect has since been attributed to defective production of interferon-gamma, a major activator of neutrophils when stimulated by interleukin (IL)12. The poor production of interferon-gamma in response to IL-12 results in the marked elevation of IgE levels (by means of unopposed IL-4 action).
Other factors in the abnormal immunologic response are described. Patients with HIE have elevated levels of granulocyte-macrophage colony-stimulating factor, which may also explain the decreased chemotaxis and increased oxygen radical production and tissue damage. Deficient suppressor T-cell numbers and activity and an imbalance in helper T cell type 1 (TH1) and helper T cell type 2 (TH2) also may play a role in an abnormal response.
Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified.2 A significantly large number of immunoglobulin-related genes were found to be up-regulated in this syndrome. Perhaps the distinct patterns may facilitate understanding of its pathophysiology and, possibly, its diagnosis.
Frequency
International
Job syndrome is a rare disorder; about 250 cases have been published.
Mortality/Morbidity
Significant morbidity is associated with Job syndrome.

The vast majority of patients have severe cutaneous and pulmonary disease, and most patients have multiple bone fractures and scoliosis.

The mortality rate is elevated because of systemic infections.
Race
The syndrome occurs in people of diverse ethnic backgrounds and does not seem to be more common in any specific population.
Sex
No sex predilection is reported.
Age
HIE usually commences in infancy, but diagnosis is often delayed until childhood or even adulthood.


CLINICAL


History
Although the diagnosis of Job syndrome is usually delayed until the patient reaches childhood or early adulthood, symptoms may begin in infancy.
Dermatologic features
o Nearly all patients have a history of moderate-to-severe, pruritic, eczematous skin eruptions in early life. The eruption does not have a seasonal variation and is present, to some degree, at all times.
o
o Intermittent episodes of staphylococcal abscesses are common. These abscesses are often referred to as cold abscesses because they do not cause pain, heat, or redness.
o
o Chronic mucocutaneous candidiasis and onychomycosis are common and usually caused by Candida species.

Systemic features
o Recurrent bronchitis is common, and a history of Staphylococcus aureus or Haemophilus influenzae pneumonia is usually associated with pneumatocele development. These pneumatoceles may become superinfected with Pseudomonas aeruginosa and Aspergillus fumigatus.
o
o Other systemic infections may occur. These may include recurrent bacterial arthritis and a staphylococcal osteomyelitis at fracture sites. A history of otitis externa, chronic otitis media, sinusitis, or multiple caries and gingivitis may also exist.
o
o Many patients report retained primary teeth, noneruption of permanent teeth, and double rows of teeth with both primary and permanent intermixed teeth.
o
o Multiple bone fractures are common and often due to unrecognized or minor trauma.
o
o Scoliosis occurs in most teenaged patients.
o
o Peripheral T-cell lymphoma has been described as a rare association with Job syndrome.3
o
o Coronary artery aneurysms have been described in patients with HIE recurrent infection syndrome.4

Physical
Dermatologic findings

o Moderate-to-severe, papular, pruritic eczematous lesions are typical; they may also be pustular and may become impetiginized. The areas of involvement predominately include the flexural areas, the area behind the ears, and the area around the hairline.
o
o Cold staphylococcal abscesses that lack the typical signs of infection appear as fluctuant masses. These abscesses may be mistaken for cysts or benign tumors. They vary in size and can occur on any part of the body.
o
o Furunculosis and cellulitis may also be present.
o
o Chronic mucocutaneous candidiasis and onychomycosis are common.
o
o A vesicular eruption similar to herpetic lesions may occur in newborns, with the more typical eczematous component developing over the next several months.
o
Systemic findings

Fever is rare. Recurrent productive cough is associated with bronchitis. Pneumonia with complicating pneumatocele development and empyema may be present, although these are less common in children who are receiving prophylactic antibiotics.

Recurrent bacterial arthritis and staphylococcal osteomyelitis may occur at fracture sites. Culture results in suspected osteomyelitis are often negative, but the findings on diagnostic images are usually consistent with this diagnosis. This osteomyelitis responds well to antibiotic treatment.

Frequent bone fractures are a feature of Job syndrome and occur in persons of all ages. The fractures usually occur in the long bones, ribs, and pelvic bones. They are often associated with an absence of pain.

Scoliosis is common. Approximately one third of patients have a spinal curvature greater than 20.

Hyperextensible joints are also common.

A characteristic coarse facies is associated with Job syndrome. The most striking features are a greater interalar width and a longer outer canthal distance. A prominent brow and supraorbital ridge with the impression of deep-set eyes is observed. These features tend to become more pronounced with age.

Causes
Although the described defects in immune response may explain the recurrent infections and chronic dermatitis, the many other congenital abnormalities are not readily explained. A single-locus autosomal dominant model of inheritance with varying expressivity is described, and the greater severity of cases in younger generations of patients may suggest genetic anticipation. Findings from a multipoint analysis confirm that the proximal 4q region contains the disease locus for Job syndrome.

DIFFERENTIALS

Atopic Dermatitis
Eosinophilic Pustular Folliculitis
Folliculitis
Gram-Negative Folliculitis
Onychomycosis
WORKUP


Lab Studies
By definition, hyper-IgE syndrome is characterized by an elevated serum IgE level.

o Levels vary, but the vast majority of patients have indices greater than 2000 IU/mL, and many patients have levels as high as 50,000 IU/mL. (Normal values of serum IgE tend to be less than 10 IU/mL in an arithmetic distribution or less than 100 IU/mL after logarithmic conversion, although these values may vary among laboratories.)
o
o Serum IgE values tend to fluctuate to some degree (most often by <50%), and, in some patients, disease activity can significantly decrease over the years.
o
o A normal IgE level should not exclude Job syndrome in an adult.
o
Serum eosinophil counts are more than 2 SDs above the normal range of values in more than 90% of patients.

Elevated eosinophil counts can be found in secretion samples, including those obtained with abscess drainage and sputum samples in cases of bronchitis or pneumonia.

No correlation is observed between the level of serum IgE and the level of serum eosinophils, and fluctuations in these levels are not associated with infections or flares of the dermatitis.

Imaging Studies
Pulmonary imaging (eg, x-ray, CT) features typically reveal recurrent alveolar lung infections; pneumatoceles; and, rarely, pneumothorax.

Radiographs of the teeth indicate the dental development age.

Other Tests
Neutrophil chemotaxis may be assessed by means of in vitro examination of their ability to move toward a chemoattractant. Such chemoattractants include endotoxin-activated serum, sodium caseinate, and formylmethionine-leucine-phenylalanine (fMet-Leu-Phe).

Although results with these tests are most often abnormal when compared with control values, chemotactic responsiveness varies, and the magnitude of the defect is less than that in other disorders (eg, Chediak-Higashi syndrome).

Histologic Findings
Histologic examination of vesicopapules may reveal an eosinophil-rich infiltration around the hair follicles, similar to that of eosinophilic pustular folliculitis.

TREATMENT



Medical Care
No definitive therapy is available for the treatment of hyper-IgE syndrome. The mainstay of treatment is the control of bacterial infections. Early incision and drainage followed by the intravenous administration of antibiotics are used for cutaneous infections. Coverage is usually aimed at Staphylococcus and Haemophilus species.
Therapy is usually longer than typical treatment because the disease in these patients responds more slowly than that of patients without Job syndrome. Intravenous antibiotic treatment for 2 weeks is typical. Chronic onychomycosis responds well to oral ketoconazole and fluconazole. Eczematous dermatitis has a varied response to high-dose topical steroids.
Chemoprophylaxis in patients with Job syndrome has varied results. Levamisole, an immunopotentiating drug, has been investigated as a therapeutic agent; in one study, it was unhelpful.

o Long-term trimethoprim-sulfamethoxazole treatment was used in one patient with recurrent pruritic dermatitis, with resolution of symptoms.
o
o Other patients treated with prophylactic antibiotics had both minor and major infections during therapy, often after several months of being infection free.
o
Cases in patients with severe hyper-IgE syndrome whose disease was unresponsive to other therapeutic modalities are reported; these cases had a marked clinical response to cyclosporin A. Treatment included low-dose cyclosporin for 6 months or longer. Both cutaneous and pulmonary infections responded to this therapy, and no adverse effects were reported.

o In one study, oral disodium cromoglycate (2 g/d) prevented the complications of Job syndrome over a 2-year period.
o Two case studies in patients with Job syndrome have shown a dramatic response in preventing infectious and eczematoid complications; patients were treated for as long as 18 months.
o
In one open-labeled study, high-dose intravenous immunoglobulin had no clear clinical benefit in 9 patients with Job syndrome. Another study showed an improvement in severe eczema along with a decrease in serum IgE levels in 2 patients after they were treated with high-dose intravenous gamma globulin.

Surgical Care
Surgical excision and drainage of cutaneous infections are often performed. Drainage is usually followed by intravenous antibiotic therapy.

Chronic hidradenitis suppurativa occurs in some patients with Job syndrome. Often, these lesions do not respond to antibiotics, and local excision may be required.

Consultations
An allergist and immunologist may help in establishing the diagnosis.

An infectious disease specialist may help in cases with infectious complications.

An orthopedist should be involved in the care of those with scoliosis and fractures.




MEDICATION


The goals of pharmacotherapy are to eradicate infections, reduce the morbidity rate, and prevent complications.
Drug Category: Antimicrobials
Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.
Drug Name Nafcillin (Nafcil, Unipen, Nallpen)
Description Initial therapy for suspected penicillin G-resistant streptococcal or staphylococcal infections. Because of thrombophlebitis, particularly in elderly patients, administer parenterally for only a short term (1-2 d); change to oral route as clinically indicated. Use for treatment of pulmonary and cutaneous infections.
Adult Dose 500 mg to 2 g IV/IM q4-6h
Alternatively, 250 mg to 1 g PO q4-6h
Pediatric Dose 0-4 kg (neonates): 10 mg/kg IM bid
4-40 kg: 25 mg/kg IM bid
Alternatively, 100-200 mg/kg/d IV/IM in 4-6 divided doses
PO dose: 50 mg/kg/d divided qid
Contraindications Documented hypersensitivity
Interactions May decrease effects of warfarin and contraceptives when administered concurrently; bacteriostatic action of tetracycline derivatives may decrease effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions To optimize therapy, determine causative organisms and susceptibility; use for >10 d to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); obtain cultures after treatment to confirm that infection is eradicated
Drug Name Oxacillin (Bactocill, Prostaphlin)
Description Bactericidal antibiotic that inhibits cell wall synthesis. Used in treatment of infections caused by penicillinase-producing staphylococci. May be used to initiate therapy in suspected staphylococcal infection. Use for treatment of pulmonary and cutaneous infections.
Adult Dose 500-1000 mg PO q4-6h
150-200 mg/kg/d IV/IM divided q6h
Pediatric Dose 50-100 mg/kg/d PO divided q6h
150-200 mg/kg/d IV/IM divided q6h; not to exceed 12 g/d
Contraindications Documented hypersensitivity
Interactions Decreases effects of contraceptives and tetracycline; concomitant disulfiram and probenecid may decrease levels; large IV doses may increase effect of anticoagulants
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in impaired renal function
Drug Name Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)
Description Bactericidal activity against susceptible organisms. Use to treat pulmonary and cutaneous infections.
Adult Dose 500 mg to 3 g IV q4-6h; not to exceed 12 g/d
500 mg to 1.5 g IM q4-6h
Pediatric Dose 100-400 mg/kg/d IV/IM divided q4-6h
Contraindications Documented hypersensitivity
Interactions Probenecid and disulfiram increase levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Drug Name Vancomycin (Lyphocin, Vancocin, Vancoled)
Description Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in treatment of septicemia and skin structure infections. Indicated for use in patients who cannot receive penicillins and cephalosporins, those whose disease did not respond to these drugs, and those who have infections with resistant staphylococci. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose, with sample drawn 0.5 h prior to next dose. Use creatinine clearance to adjust dose in renal impairment. Use for treatment of pulmonary and cutaneous infections.
Adult Dose 500 mg to 2 g/d IV divided tid/qid for 7-10 d
Pediatric Dose 40 mg/kg/d IV divided tid/qid for 7-10 d
Contraindications Documented hypersensitivity
Interactions Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; with concurrent aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; coadministration of nondepolarizing muscle relaxants may enhance effects in neuromuscular blockade
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal failure, neutropenia; "red man" syndrome is caused by too rapid IV infusion (dose given over a few minutes) but rarely happens when dose given IV over 2 h administration or as PO or IP administration; "red man" syndrome is not an allergic reaction
Drug Name Cefazolin (Ancef, Kefzol, Zolicef)
Description First-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. Primarily active against skin flora, including S aureus. Typically used alone for skin and skin-structure coverage. IV and IM dosing regimens are similar. Use for treatment of pulmonary and cutaneous infections.
Adult Dose 250 mg to 2 g IV/IM q6-12h, depending on severity of infection; not to exceed 12 g/d
Pediatric Dose 25-100 mg/kg/d IV/IM divided q6-8h, depending on severity of infection; not to exceed 6 g/d
Contraindications Documented hypersensitivity
Interactions Probenecid prolongs effect; coadministration with aminoglycosides may increase renal toxicity; may yield false-positive results with urine-dip test for glucose
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged or repeated therapy
Drug Name Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS)
Description Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. For prevention and/or suppression of inflammatory symptoms of Job syndrome.
Adult Dose 160 mg TMP/800 mg SMZ PO q12h for 10-14 d
Pediatric Dose <2 months: Do not administer
>2 months: 10-20 mg TMP/kg/d PO/IV divided tid/qid for 14 d
Contraindications Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Interactions May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Discontinue at first appearance of new skin rash or adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with long-term alcoholism, elderly patients, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation
Drug Name Cyclosporine (Sandimmune, Neoral)
Description Helpful in a variety of skin disorders. For prevention and/or suppression of inflammatory symptoms of Job syndrome.
Adult Dose 2.5-5 mg/kg/d PO in divided doses
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis (may increase risk of cancer)
Interactions Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgia rates increase with concurrent lovastatin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; use IV only for those who cannot take medication PO
Drug Category: Antifungals
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.
Drug Name Fluconazole (Diflucan)
Description Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, preventing conversion of lanosterol to ergosterol and thereby disrupting cellular membranes. For treatment of fungal infections in Job syndrome, including onychomycosis.
Adult Dose 150 mg PO once or 400 mg qd, depending on severity of infection
Pediatric Dose 3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg qd, depending on severity of infection
Contraindications Documented hypersensitivity
Interactions Hydrochlorothiazides may increase levels; long-term coadministration of rifampin may decrease levels; coadministration may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with coadministration; cyclosporine concentrations may increase when administered concurrently
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adjust dose in renal insufficiency; monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) or multiple concomitant medications; not recommended for breastfeeding mothers
Drug Name Ketoconazole (Nizoral)
Description Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death. For treatment of fungal infections in Job syndrome, including onychomycosis.
Adult Dose 200 mg PO qd; increase to 400 mg PO qd, if clinically indicated
Pediatric Dose <2 years: Not established
>2 years: 3.3-6.6 mg/kg/d PO once
Contraindications Documented hypersensitivity; fungal meningitis
Interactions Isoniazid may decrease bioavailability; coadministration decreases rifampin or ketoconazole effects; may increase toxicity of anticoagulants, corticosteroids, and cyclosporine (can adjust cyclosporine dosage); may decrease theophylline levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after dose

FOLLOW-UP


Further Outpatient Care
Extra vigilance may be required in routine screening of these patients for scoliosis.

If a school-based program exists, healthcare providers should be made aware of the patient's greater-than-typical risk of scoliosis.

Early detection with proper care can prevent progression.

Deterrence/Prevention
Initiate treatment at the first signs of infection to prevent long-term complications.

Regularly screen patients for scoliosis so that early noninvasive treatment can be used.

Prognosis
Few data are available on the prognosis of patients with Job syndrome.

Many patients who are undergoing regular monitoring and receiving appropriate treatment will live beyond the age of 50 years.

Death is often due to infectious complications.

Patient Education
Educate patients about the importance of recognizing the early signs of infection so that treatment can be initiated as soon as possible.

Mild local pain should be considered a sign of possible infection, and patients should be taught that the typical inflammatory response does not necessarily occur.




Medical/Legal Pitfalls
Physicians should be aware that a normal IgE level does not exclude Job syndrome in an adult.

If the patient's history is suggestive of this disorder, a complete workup is still in order.

The threshold for suspected abscesses should be lower in patients with hyper-IgE syndrome because few, if any, signs of inflammation are usually present.