Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

Clinical trial: Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job's) Syndrome

Summary: 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.

Detailed description: 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.

Eligibility: -  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.

Relevance to patient case: not relevant