Hyperimmunoglobulin E syndrome

BACKGROUND

Hyperimmunoglobulin E syndrome (HIES), also called Job syndrome, is an inherited immunodeficiency that is characterized by recurrent bacterial infections, skin abscesses, and high levels of immunoglobulin E (IgE). Immunoglobulin (Ig), also called antibodies, is secreted by immune system cells to detect antigens (foreign substances like bacteria and viruses that enter the body). Once the antibodies attach to the antigen, white blood cells destroy the antigen.

Even though HIES patients have high levels of IgE in their blood, they are vulnerable to infection and disease because other important immune cells do not function properly. HIES patients are born with abnormal T-cells (type of white blood cells) that are unable to produce enough interferon-gamma, which stimulates white blood cells called macrophages to engulf foreign invaders. Consequently, the immune system's response to antigens is delayed.

Studies suggest that HIES is a genetic disorder that can be inherited as either an autosomal dominant (AD-HIES) or autosomal recessive (AR-HIES) trait. However, the specific gene involved remains unidentified.

HIES is an extremely rare disease, with only 250 cases ever reported internationally. Most individuals are not diagnosed until childhood, or sometimes adulthood.

The oldest reported HIES patient was 60 years old. Most patients die between the ages of 20 and 30 from severe pulmonary (lung) infections and diseases like aspergillosis (fungal infection).

Currently, there is no known cure for HEIS. Treatment focuses on controlling recurrent infections. Depending on the cause of infections, patients receive antibiotics, antivirals, or antifungals. In addition, intravenous immunoglobulin (IVIG), which are blood products containing antibodies, may help boost the immune system temporarily when severe infections occur.

CAUSES

Although the exact cause of hyperimmunoglobulin E syndrome (HIES) remains unknown, studies suggest that it is a genetic disorder that can be inherited as either an autosomal dominant or autosomal recessive trait. However, the specific gene involved remains unidentified.

In order to inherit the disorder as an autosomal recessive disorder, one mutated gene from each parent must be inherited. Individuals who only have one mutated gene and do not express symptoms are called carriers.

Carriers have a 50% chance of passing the abnormal gene to each of their children. If both parents are carriers of LAD, there is a 25% chance that each of their children will inherit the disease and a 50% chance that each of their children will be a carrier.

In order to inherit the disorder as an autosomal dominant disorder, the child only needs to inherit one mutated gene. Individuals who have the disease have a 50% of passing the disease on to each of their children.

Researchers believe that Staphylococcus aureus is the most common trigger of infections associated with HIES. Other common pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Candida albicans, and the herpes virus.

SYMPTOMS

General: Symptoms and infections associated with HIES typically occur during infancy, but most individuals are not diagnosed until childhood, or sometimes adulthood.

Symptoms: Common symptoms of HIES include persistent skin abscesses and infection, recurrent pus in the sinuses, eczema (skin rash), itchy skin, and painless skin abscesses (infections).

Patients who have inherited HIES as an autosomal dominant trait often suffer from skeletal and dental abnormalities such as scoliosis (curved spine), fractured bones (which often go unrecognized because they cause little or no pain), bone and teeth defects, and late shedding and fractures of baby teeth.

Infections: Patients often suffer from recurrent infections such as fungal infections of the mouth and nails, bronchitis, pneumonia, ear infections, sinus infections, bone infections, and gingivitis (gum disease). A history of Staphylococcus aureus or Haemophilus influenzae pneumonia is usually associated with the development of cavities (spaces) in the lungs. These cavities may become re-infected with Pseudomonas aeruginosa and Aspergillus fumigatus.

DIAGNOSIS

Enzyme-linked immunosorbent assay (ELISA): The standard diagnostic test for HEIS is an enzyme-linked immunosorbent assay (ELISA), which detects the level of antibodies in the blood. A healthcare provider sends a sample of the patient's blood to a testing laboratory. Patients are diagnosed with HIES if they have an IgE level greater than two standard deviations higher than normal, and they suffer from characteristic symptoms.

Computerized tomography (CT) scan: Once a patient is diagnosed, a computerized tomography (CT) scan of the lungs is performed to detect possible cavities in the lungs. These cavities occur in almost 80% of HIES patients and they may become re-infected with organisms like Pseudomonas aeruginosa and Aspergillus. CT scans are performed at the hospital and a large X-ray machine takes pictures of the lungs at various angles.

TREATMENT

General: There is currently no treatment for hyperimmunoglobulin E syndrome (HEIS). Instead, treatment focuses on relieving symptoms and resolving infections associated with the disorder. Treatment of infections is generally longer in HIES patients than in the general population because they respond slower. Patients typically receive intravenous antimicrobials or antifungals for about two weeks.

Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. Also, patients should take medications exactly as prescribed by their doctors. If treatment is discontinued too quickly, the infection may recur.

Antibacterials: Antibacterial agents, such as nafcillin (Nafcil©, Unipen© or Nallpen©), oxacillin (Bactocill© or Prostaphlin©), ampicillin (Marcillin©, Omnipen©, Polycillin©, Principen©, or Totacillin©), vancomycin (Lyphocin©, Vancocin©, or Vancoled©), cefazolin (Ancef©, Kefzol© or Zolicef©), sulfamethoxazole and trimethoprim (Bactrim©, Bactrim DS©, Septra©, and Septra DS©), and cyclosporine (Sandimmune© or Neoral©), have been used to treat bacterial infections commonly associated with HIES.

Antifungals: Antifungals, such as fluconazole (Diflucan©) and Ketoconazole (Nizoral©), have been used to treat fungal infections commonly associated with HIES.

Intravenous immunoglobulin therapy (IVIG): Intravenous immunoglobulin therapy (IVIG) may help to build up the immune system temporarily when patients have severe infections. Intravenous immunoglobulin (IVIG) is made of antibodies extracted from pooled blood donations from hundreds to thousands of donors. The immunoglobulin is typically injected into the patient's vein for about two to four hours a day for two to seven days. The patient usually receives another single dose every 10-21 days or every three to four weeks depending on the severity of the condition. Patients typically start responding to treatment after about eight days. The effects of treatment are temporary. Therefore, continual treatments are necessary to help boost the immune system.

INTEGRATIVE THERAPIES

Good scientific evidence :

Ginseng : Several studies suggest that ginseng can effectively enhance immune system function.

Avoid ginseng if known allergy to plants in the Araliaceae family. There has been a report of a serious life-threatening skin reaction, possibly caused by contaminants in the ginseng formulation.

Zinc : Zinc appears to be an essential trace element for the immune system, but research on the effect of zinc supplementation on immune function is scant and mostly focuses on patients with specific diseases. Zinc gluconate appears to exert beneficial effects on immune cells, improving CD3 and CD4 counts, and increasing CD4/CD8 define ratios in children. There are relatively few studies that examine zinc levels and the effects of zinc supplementation on the health of the elderly population. Further research is needed before a firm conclusion can be made.

Zinc is generally considered safe when taken at the recommended dosages. Avoid zinc chloride, since studies have not been done on its safety or effectiveness. While zinc appears safe during pregnancy in amounts lower than the established upper intake level, caution should be used because studies cannot rule out the possibility of harm to the fetus.

Unclear or conflicting scientific evidence :

Arginine (L-arginine) : Preliminary research results suggest that arginine supplementation may enhance the immune response elicited by the pneumococcal vaccine in older people. More studies are needed to confirm these results.

Avoid if allergic to arginine. Avoid with history of stroke, liver disease, or kidney disease. Avoid if pregnant or breastfeeding. Use cautiously if taking blood-thinning drugs (like warfarin), blood pressure drugs, or herbs or supplements with similar effects. Check blood potassium levels.

Astragalus : Astragalus has been suggested as an immune system stimulant in preliminary laboratory and animal research, and in traditional accounts. Reliable human studies are lacking. High quality human research is necessary before a firm conclusion can be drawn.

Avoid if allergic to astragalus, peas, or any related plants or with a history of Quillaja bark-induced asthma. Avoid with aspirin, aspirin products, or herbs or supplements with similar effects. Avoid with inflammation (swelling), fever, stroke, transplant, or autoimmune diseases (like HIV/AIDS). Stop use two weeks before surgery/dental/diagnostic procedures with a risk of bleeding and avoid use immediately after these procedures. Use cautiously with bleeding disorders, diabetes, high blood pressure, lipid disorders, or kidney disorders. Use cautiously with blood-thinners, blood sugar-altering agents, diuretics, or herbs and supplements with similar effects. Avoid if pregnant or breastfeeding.

Beta-carotene : Preliminary research of beta-carotene for immune system maintenance or stimulation shows mixed results. Further research is needed before a conclusion can be drawn. Avoid if sensitive to beta-carotene, vitamin A, or any other ingredients in beta-carotene products.

Cat's claw : A few early studies suggested that cat's claw may boost the immune system. However, results from different studies have not agreed with each other. Further research is needed before a firm conclusion can be made.

Avoid if allergic to Cat's claw or Uncaria plants or plants in the Rubiaceae family, such as gardenia, coffee, or quinine. Avoid with history of conditions affecting the immune system (such as AIDS, HIV, some types of cancer, multiple sclerosis, tuberculosis, rheumatoid arthritis, lupus). Use cautiously with bleeding disorders, history of stroke, or if taking drugs that may increase the risk of bleeding. Stop use two weeks before surgery/dental/diagnostic procedures with bleeding risk, and do not use immediately after these procedures. Avoid if pregnant or breastfeeding. Cat's claw may be contaminated with other Uncaria species. Reports exist of the potentially toxic Texan grown plant Acacia gregii being substituted for cat's claw.

Copper : Copper is involved in the development of immune cells and immune function in the body. Severe copper deficiency appears to have adverse effects on immune function, although the exact mechanism is unclear.

Avoid if allergic/hypersensitive to copper. Avoid use of copper supplements during the early phase of recovery from diarrhea. Avoid with hypercupremia occasionally observed in disease states including cutaneous leishmaniasis, sickle-cell disease, unipolar depression, breast cancer, epilepsy, measles, Down syndrome, and controlled fibrocalculous pancreatic diabetes (a unique form of secondary diabetes mellitus). Avoid with genetic disorders affecting copper metabolism such as Wilson's disease, Indian childhood cirrhosis, or idiopathic copper toxicosis. Avoid with HIV/AIDS. Use cautiously with water containing copper concentrations greater than 6 milligrams/liter. Use cautiously with anemia, arthralgia, and myalgia. Use cautiously if taking oral contraceptives. Use cautiously if at risk for selenium deficiency. The U.S. recommended dietary allowance (RDA) is 1,000 micrograms for pregnant women. The RDA is 1,300 micrograms for breastfeeding women.

Echinacea : Echinacea has been studied alone and in combination preparations for immune system stimulation (including in patients receiving cancer chemotherapy). It remains unclear if there are clinically significant benefits. Additional studies are needed in this area before conclusions can be drawn regarding safety or effectiveness.

Avoid if allergic to plants in the Asteraceae or Compositae family (ragweed, chrysanthemums, marigolds, daisies). Avoid Echinacea injections. Avoid if history of liver disease or if taking amoxicillin. Avoid in transplant patients. Use cautiously if driving or operating heavy machinery or if history of asthma, diabetes, conditions affecting the immune systems (lupus, TB, AIDS-HIV), and rheumatologic conditions (rheumatoid arthritis). Avoid if pregnant or breastfeeding. Tinctures may contain large amounts of alcohol.

Gamma linolenic acid (GLA) : Few clinical trials have investigated the effects of GLA on immune responses in healthy human subjects. Results from one randomized, clinical trial suggest that GLA, as blackcurrant seed oil, may offer some benefits. Further well-designed clinical trials are required before definite conclusions can be made.

Use cautiously with drugs that increase the risk of bleeding like anticoagulants and anti-platelet drugs. Avoid if pregnant or breastfeeding.

Goldenseal : Goldenseal is sometimes suggested to be an immune system stimulant. However, there is little human or laboratory evidence in this area. More research is needed before a firm conclusion can be drawn.

Avoid if allergic or hypersensitive to goldenseal or any of its constituents, such as berberine and hydrastine. Use cautiously with bleeding disorders, diabetes, or low blood sugar. Avoid if pregnant or breastfeeding.

Maitake mushroom : Animal and laboratory studies suggest that beta-glucan extracts from maitake may alter the immune system. Maitake has not been studied thoroughly in humans, and its effects are not well known. Because it has been used historically as a food, it is thought that low doses may be safe. Avoid if allergic or hypersensitive to Grifola frondosa (maitake). Use cautiously with a history of low blood pressure, diabetes, or with drugs, herbs, or supplements that treat such conditions. Avoid if pregnant or breastfeeding.

Massage : Preliminary evidence suggests that massage therapy may preserve immune function. Further research is needed before a firm conclusion can be made.

Avoid with bleeding disorders, low platelet counts, or if taking blood-thinning medications (such as heparin or warfarin). Areas should not be massaged where there are fractures, weakened bones from osteoporosis or cancer, open/healing skin wounds, skin infections, recent surgery, or blood clots. Use cautiously with history of physical abuse or if pregnant or breastfeeding. Massage should not be used as a substitute for more proven therapies for medical conditions. Massage should not cause pain to the client.

Meditation : Preliminary research reports increased antibody response after meditation. Further study is needed to confirm these findings.

Use cautiously with underlying mental illnesses. People with psychiatric disorders should consult with their primary mental healthcare professional(s) before starting a program of meditation, and should explore how meditation may or may not fit in with their current treatment plan. Avoid with risk of seizures. The practice of meditation should not delay the time to diagnosis or treatment with more proven techniques or therapies, and should not be used as the sole approach to illnesses.

Mistletoe : A few small trials found mistletoe to be promising as an immunostimulant in individuals with the common cold. Further research is needed to confirm these results.

Avoid if allergic or hypersensitive to mistletoe or to any of its constituents. Anaphylactic reactions (life threatening) have been described after injections of mistletoe. Avoid with acute highly febrile inflammatory disease, thyroid disorders, seizure disorders, or heart disease. Use cautiously with diabetes, glaucoma, or with cholinergics.

Probiotics : Lactobacillus in fermented milk, low-fat milk, or lactose-hydrolyzed low-fat milk may enhance immune function. Bifidobacterium may as well, including in the elderly. However, commercially produced yogurt may not yield similar benefits. There is some evidence that probiotics added during food preparation (e.g. waffles with Enterococcus faecium M-74 added) can enhance immune functioning. More studies are needed, particularly with yogurt, before a firm conclusion can be made.

Probiotics are generally considered safe and well-tolerated. Avoid if allergic or hypersensitive to probiotics. Use cautiously if lactose intolerant.

Vitamin A (retinol) : Vitamin A deficiency may compromise immunity, but there is no clear evidence that additional vitamin A supplementation is beneficial for immune function in patients who are not vitamin A deficient.

Avoid if allergic or hypersensitive to vitamin A. Vitamin A toxicity can occur if taken at high dosages. Use cautiously with liver disease or alcoholism. Smokers who consume alcohol and beta-carotene may be at an increased risk for lung cancer or heart disease. Vitamin A appears safe in pregnant women if taken at recommended doses. Use cautiously if breastfeeding because the benefits or dangers to nursing infants are not clearly established.

Vitamin B6 (pyridoxine) : Vitamin B6 is important for immune system function in older individuals. One study found that the amount of vitamin B6 required to reverse immune system impairments in elderly people was more than the current recommended dietary allowance (RDA). Well-designed clinical trials on vitamin B6 supplementation for this indication are needed before a recommendation can be made.

Some individuals seem to be particularly sensitive to vitamin B6 and may have problems at lower doses. Avoid excessive dosing. Vitamin B6 is likely safe when used orally in doses not exceeding the recommended dietary allowance (RDA). The RDA for pregnant women is 1.9 milligrams per day. There is some concern that high-dose pyridoxine taken by a pregnant mother can cause seizures in a newborn. The RDA in breastfeeding women is 2 milligrams per day.

Vitamin E : Studies of the effects of vitamin E supplementation on immune system function have yielded mixed results. Further research is needed before a clear conclusion can be drawn.

Avoid if allergic or hypersensitive to vitamin E. For short periods of time, vitamin E supplementation is generally considered safe at doses up to 1,000 milligrams per day. Avoid doses higher than 1,000 milligrams a day. Avoid with retinitis pigmentosa (loss of peripheral vision). Use cautiously with bleeding disorders. The recommended dose of vitamin E for pregnant women of any age is 15 milligrams, and it is 19 milligrams for breastfeeding women of any age. Use beyond this level in pregnant women is not recommended.

Fair negative scientific evidence :

DHEA (dehydroepiandrosterone) : DHEA (dehydroepiandrosterone) is a naturally occurring hormone that is produced by the adrenal glands. Some textbooks and review articles have suggested that DHEA can stimulate the immune system. However, current scientific evidence does not support this claim.

Avoid if allergic to DHEA. Avoid with a history of seizures. Use cautiously with adrenal or thyroid disorders or if taking anticoagulants, or drugs, herbs, or supplements for diabetes, heart disease, seizure, or stroke. Stop use two weeks before surgery/dental/diagnostic procedures with bleeding risk and do not use immediately after these procedures. Avoid if pregnant or breastfeeding.

Lycopene : It has been proposed that lycopene and other carotenoids, such as beta-carotene, may stimulate the immune system. However, several studies of lycopene supplements and tomato juice intake in humans report no effects on the immune system.

Avoid if allergic to tomatoes or to lycopene. Due to a lack of conclusive data, avoid if pregnant or breastfeeding.

PREVENTION

Currently, there is no known method of prevention of HIES. Patients who have the disease may wish to speak with their healthcare providers about the risk of having a child with the disease.

Patients can take precautions to avoid contracting infections associated with the disease. Patients should thoroughly wash their hands with soap and water. Patients should talk to their healthcare providers about recommended immunizations. Patients should avoid close contact with individuals who have contagious illnesses because they have an increased risk of contracting infections.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

• DermNet NZ. http://dermnetnz.org. Accessed April 12, 2007.
• Immune Deficiency Foundation. www.primaryimmune.org. Accessed April 12, 2007.
• National Organization for Rare Disorders. www.rarediseases.org. Accessed April 12, 2007.
• Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com. Copyright © 2007. Accessed April 12, 2007.
• Rosenberg, Benjamin. Hyperimmunoglobulin E Syndrome. Dermatol Online J. 2004 Nov 30;10(3):4 .View abstract