Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job's) Syndrome
Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job's) Syndrome
This study will examine the safety and effectiveness of ranitidine (Zantac) in patients with
 Hyper-IgE recurrent infection syndrome, a disease characterized by recurrent infections of
 the ears, sinuses, lungs and skin, and abnormal levels of the antibody immunoglobulin E
 (IgE).

 Patients age 2 and older who have Hyper-IgE recurrent infection syndrome and who have had
 chronic or frequent infections in the last 12 months may be eligible for this study.

 Participants are randomly assigned to take ranitidine or placebo in pill or liquid form twice
 a day for 12 months. In addition to treatment, patients undergo the following procedures
 during visits scheduled on day 0 of the study (baseline) and at 3, 12, 15 and 24 months.
 Evaluations at 6, 9, 18 and 21 months are by telephone.

 -  Medical history and physical examination - baseline and 3 and 24 months.

 -  Clinical severity score - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

 -  Dermatology exam - baseline and 3, 12, 15 and 24 months.

 -  Pulmonary function test - baseline and 12 and 24 months.

 -  Chest CT - baseline and 12 and 24 months.

 -  Quality of life assessment - baseline and 3, 12, 15 and 24 months.

 -  Pregnancy testing - baseline and 3, 12, 15 and 24 months.

 -  HIV test - baseline and 12 and 24 months.

 -  Contraception evaluation - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

 -  Missed school/work days assessment - baseline and 3, 12, 15 and 24 months.

 -  Medication adherence - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

 In addition to the above procedures, participants who are not enrolled in study 00-I-0159
 have a baseline scoliosis series and genetic consult.
Hyper-immunoglobulin E (IgE) syndrome (HIES) is a rare primary immunodeficiency characterized
 by eczema, recurrent skin and lung infections, elevated serum IgE, and multiple connective
 tissue and skeletal abnormalities. The autosomal dominant form of HIES is caused primarily by
 a mutation in the STAT3 gene. Patients with HIES produce IgE antibodies specific for Candida
 albicans and Staphylococcus aureus, two of the common pathogens in this population. We
 hypothesize that the presence of pathogen-specific IgE, combined with continuous exposure to
 these ubiquitous agents, leads to chronic IgE-mediated histamine release from basophils and
 mast cells, with subsequent pathogen-specific immune tolerance and an increase in
 pathogen-specific T regulatory cells. We plan to test this hypothesis through clinical and
 immunologic evaluation of HIES patients before, during, and after histamine-2 receptor (H2)
 blocker therapy with ranitidine through a prospective, placebo-controlled crossover study. We
 chose this therapy because histamine has been shown to stimulate interleukin-10 (IL-10), a
 major down regulatory cytokine, through the H2 receptor, and clinical improvement has been
 observed in several patients treated with H2 blockers. Laboratory studies will include
 determinations of pathogen-specific immunoglobulin G4 (IgG4):IgE ratios, basophil activation,
 IL-10 producing regulatory T-cells, cellular proliferative responses to staphylococcal and
 candidal antigens, and functional testing of regulatory T-cells. Clinical evaluations will
 include comprehensive history and physical examination, dermatologic evaluation, genetic
 evaluation for clinical severity scoring of HIES, pulmonary function tests, and chest
 computerized tomography (CT) examination. Through this study, we will further our
 understanding of the immunologic abnormalities of HIES and determine whether a larger
 prospective, double-blind trial of H2 blockade as adjunctive therapy for HIES is indicated.
-  INCLUSION CRITERIA:

 1. Male and female patients with the diagnosis of Hyper IgE Recurrent Infection
 (Job) syndrome. Mutations in the STAT3 gene account for the majority, if not all
 cases of HIES. However as the full genetics of HIES remains unknown, we will use
 clinical criteria, including the expert opinion of the investigators, as well as
 a score greater than 40 by the diagnostic scoring system used in protocol
 00-I-0159.

 2. A chronic (greater than 4 weeks duration) infection or greater than 2 acute
 infections within the last 12 months. Acute infections can include but are not
 limited to: pneumonia, abscesses, sinusitis, skin infections, mucocutaneous
 candidiasis and ear infections. Chronic infections include continuous or
 intermittent symptoms despite appropriate therapeutic interventions for at least
 4 weeks, including but not limited to chronic lung infiltrates with productive
 cough, chronic ear drainage despite topical therapy, chronic or intermittent
 drainage from a single abscess site, and/or chronic signs of sinusitis on sinus
 CT scan.

 3. Patients aged 2 years and above. There is no upper age limit. We are excluding
 children less than 2 years of age, as we do not expect them to meet the first
 inclusion criterion, having a score high enough to be diagnosed with HIES.

 4. Patients have to be at their own personal clinical baseline for at least 2 weeks
 duration. Patients will not start the study medication during an acute
 exacerbation of and infection.

 5. The patient or the patient's guardian will be willing and capable of providing
 informed consent after initial counseling by clinical staff. Separate consent
 forms for all interventional procedures will be obtained after explanation of the
 specific procedure.

 6. Patients must agree to have blood stored for future studies of the immune system
 and/or other medical conditions.

 7. Women of childbearing potential must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry
 and for the duration of study participation.

 8. Patients may be concurrently enrolled on other protocols as long as the Principal
 Investigator (PI) is informed.

 EXCLUSION CRITERIA:

 1. Pregnancy. Ranitidine is pregnancy class B, and likely safe in pregnancy, but as this
 has not been studied, pregnant patients will be excluded. In addition, hormonal
 changes that occur during pregnancy may affect the skin manifestations and frequency
 of infection.

 2. Hypersensitivity to ranitidine or any of the ingredients in ranitidine.

 3. Pre-existing medications or conditions for which the investigators judge that
 ranitidine should not be given.

 4. Patient or investigators unwilling to stop baseline H2 receptor antagonist therapy
 (over the counter or prescription) such as Tagamet (Cimetidine), Pepcid (Famotidine),
 and Axid (Nizatidine). H2 receptor antagonist therapy must be stopped for 3 months
 prior to study initiation. Patients who are receiving H2 receptor antagonist therapy
 for gastritis, acid reflux, or peptic ulcer disease will be offered changing their
 regimen to a proton pump inhibitor or other non-H2 receptor antagonist therapy to
 allow for study enrollment (3 months after stopping the H2 receptor antagonist).

 5. Patients under the age of 2 years

 6. Patients with HIV, receiving chemotherapy or who have a malignancy.

 7. Any condition that in the judgment of the investigator would place the subject at
 undue risk or compromise the results or interpretation of the study.