eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
Omenn Syndrome: Treatment & Medication
Updated: Jan 13, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Conventional care for any patient with severe combined immunodeficiency (SCID) includes isolation to prevent infection and also meticulous skin and mucosal hygienic care while the patient is awaiting stem cell reconstitution. Signs of sepsis and pulmonary infections may be subtle; thus, fever alone requires a detailed search for infectious agents. Empirical broad-spectrum antibiotics are administered parenterally while cultures and body fluid analyses are in progress. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis. In individual cases, prophylaxis with antiviral agents (eg, acyclovir) or antibiotics may be appropriate. Parenteral nutrition is customarily provided as therapy for diarrhea and failure to thrive.
Bone marrow or other stem cell reconstitution is first-line conventional therapy for most forms of SCID, including Omenn syndrome, although the mortality rate is higher when compared to other types of SCID. Workup includes major histocompatibility complex (MHC) typing to identify a fully matched sibling, or, in the case of consanguinity, possibly a parent. Reconstitution by using a matched unrelated donor or haploidentical parent has also been successful, although more complications and higher mortality have been reported. Preparatory immunosuppression of malfunctioning activated T cells has decreased the incidence of graft failure in Omenn syndrome. Nutritional support and T-cell suppression prior to BMT may reduce the risk of complications. Pretransplantional evaluation routinely includes testing of the recipient and the donor for infectious agents, such as cytomegalovirus (CMV), HIV, and hepatitis viruses.
Specific therapy for dermatitis and eosinophilia in Omenn syndrome is immunosuppression with cyclosporine. Interferon gamma has been administered in an attempt to down-regulate interleukin 4 (IL-4) and interleukin 5 (IL-5) production by the oligoclonal Th2 cells. Interferon gamma may independently modulate the inflammatory reaction by enhancing phagocytic functions.
Ancillary therapy includes intravenous immunoglobulin (IVIG) replacement. Live viral vaccines should not be administered.
In the future, the identification of the recombinase mutations as the cause of Omenn syndrome should enable gene transfer therapy. At this time, successful gene therapy is available only for the X-linked T-B+ form of SCID, in which mutations in the common g chain are necessary for function of the cell surface receptors of interleukin 2 (IL-2), IL-4, interleukin 7 (IL-7), interleukin 9 (IL-9), and interleukin 15 (IL-15).
Surgical Care
Surgical intervention is not routinely considered.
Consultations
Promptly initiate workup for stem cell reconstitution with the bone marrow transplant (BMT) team. In the meantime, consult a gastroenterologist and a nutritionist for important support.
Diet
A patient with chronic diarrhea and a failure to thrive requires consultation with a gastroenterologist and nutritionist to adequately provide calories, nutrients, and vitamins. Parenteral or enteral nutrition supplementation is usually necessary.
Activity
Infants with any form of SCID should be isolated to decrease the risk of common viral and bacterial infections. Patients should avoid crowds in locations such as stores, doctors' offices, and hospitals, and they and their caregivers should engage in customary hygiene practices such as strict hand washing.
Medication
Overview
Specific therapy for dermatitis and lymphadenitis involves immunosuppression with cyclosporine and the down-regulation of interleukin 4 (IL-4) and interleukin 5 (IL-5) with interferon gamma. Broad-spectrum antibiotics are needed to treat invasive infections, especially those due to the common S aureus and gram-negative enteric bacteria. Prophylactic antibiotics and antifungal agents are often appropriate. Ancillary treatment with intravenous immunoglobulin (IVIG) replacement further decreases the risk of infection. Nutritional supplementation is mandatory to decrease the risk of infection and increase the likelihood of successful stem cell reconstitution.
Because Omenn syndrome tends to be fatal unless treated. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a curative approach, but treatment-related complications and graft rejection must be overcome. One successful innovative effort used reduced-intensity conditioning allogeneic HSCT from a sibling donor, achieving full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation.6 Although HSCT is the treatment of choice, allogeneic cord blood transplantation is another option recently used in one child.7
Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies
The overall consensus among clinical immunologists is that an intravenous immunoglobulin (IVIG) dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable.8 Patients with meningoencephalitis (X-linked agammaglobulinemia) require higher doses (1 g/kg) and, perhaps, intrathecal therapy. The measurement of preinfusion (ie, trough serum IgG levels every 3 mo until a steady state is achieved and then every 6 mo if the patient is stable) may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons in whom the catabolism of infused immunoglobulin G (IgG) is high, more frequent (eg, every 2-3 wk) infusions of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during active infection; measuring serum IgG levels and adjusting to higher doses or shorter intervals may be required.
For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes (eg, solvent detergent versus pasteurization and liquid versus lyophilized) are recognized. The choice of brands may depend on the hospital or home care formulary and on local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording of all adverse effects that occur during the infusion is crucial.
Periodic liver and renal function testing, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) advises that, in patients at risk for renal failure, the recommended doses should not be exceeded and that infusion rates and concentrations should be the practical minimum levels. Examples of patients at risk for renal failure include those older than 65 years; those who use nephrotoxic drugs; and those with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia.
The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and in those in whom immune complexes form. In patients with active infection, infusion rates may need to be slower, and the dose halved (ie, 200-300 mg/kg). The remaining half should be given the next day to achieve a full dose. Treatment should not be discontinued. After normal serum IgG levels are achieved, adverse reactions are uncommon unless patients have active infections.
With the new generation of IVIG products, adverse effects are reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency and patients with active infections have more severe reactions.
The anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with fragment crystallizable (Fc) receptors and that trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose; maximum, 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, therapy with analgesics and antihistamines may be repeated.
Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products with sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg/kg/min based on the amount of sucrose. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring the blood urea nitrogen and creatinine levels before starting the treatment and prior to each infusion is necessary. If the patient's renal function deteriorates, the treatment should be discontinued.
Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few cases of true anaphylaxis have been reported in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience this is rare. In addition, this is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or in those with severe combined immunodeficiency (SCID). Caution should be exercised in patients with IgA deficiency (<7 mg/dL) who need IVIG because of IgG-subclass deficiencies. IVIG preparations with low concentrations of contaminating IgA are advised (see the Table below).
Immune Globulin, Intravenous9,10,8,11
Open table in new window
Table
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | Parenteral Form and Final Concentrations | IgA Content (mcg/mL) |
| Carimune NF (CSL Behring) | Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration | 6.4-6.8 | 6% solution: 10% sucrose, <20 mg NaCl/g protein | Lyophilized powder 3%, 6%, 9%, 12% | Trace |
| Flebogamma (Grifols USA) | Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization | 5.1-6 | Sucrose free, contains 5% D-sorbitol | Liquid 5% | <50 |
| Gammagard Liquid 10% (Baxter Bioscience) | Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation | 4.6-5.1 | 0.25M glycine | Ready-for-use Liquid 10% | 37 |
| Gamunex (Talecris Biotherapeutics) | Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation | 4-4.5 | Contains no sugar, contains glycine | Liquid 10% | 46 |
| Iveegam EN (Baxter Bioscience) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% glucose, 0.3% NaCl | Lyophilized powder 5% | <10 |
| Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) | Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated | 6.4-7.2 | 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose | Lyophilized powder 5%, 10% | <1.6 (5% solution) |
| Octagam (Octapharma USA) | Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization | 5.1-6 | 10% maltose | Liquid 5% | 200 |
| Panglobulin (Swiss Red Cross for the American Red Cross) | Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration | 6.6 | Per gram of IgG: 1.67 g sucrose, <20 mg NaCl | Lyophilized powder 3%, 6%, 9%, 12% | 720 |
| Privigen Liquid 10% (CSL Behring) | Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration | 4.6-5 | L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) | Ready-for use liquid 10% | <25 |
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | Parenteral Form and Final Concentrations | IgA Content (mcg/mL) |
| Carimune NF (CSL Behring) | Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration | 6.4-6.8 | 6% solution: 10% sucrose, <20 mg NaCl/g protein | Lyophilized powder 3%, 6%, 9%, 12% | Trace |
| Flebogamma (Grifols USA) | Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization | 5.1-6 | Sucrose free, contains 5% D-sorbitol | Liquid 5% | <50 |
| Gammagard Liquid 10% (Baxter Bioscience) | Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation | 4.6-5.1 | 0.25M glycine | Ready-for-use Liquid 10% | 37 |
| Gamunex (Talecris Biotherapeutics) | Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation | 4-4.5 | Contains no sugar, contains glycine | Liquid 10% | 46 |
| Iveegam EN (Baxter Bioscience) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% glucose, 0.3% NaCl | Lyophilized powder 5% | <10 |
| Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) | Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated | 6.4-7.2 | 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose | Lyophilized powder 5%, 10% | <1.6 (5% solution) |
| Octagam (Octapharma USA) | Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization | 5.1-6 | 10% maltose | Liquid 5% | 200 |
| Panglobulin (Swiss Red Cross for the American Red Cross) | Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration | 6.6 | Per gram of IgG: 1.67 g sucrose, <20 mg NaCl | Lyophilized powder 3%, 6%, 9%, 12% | 720 |
| Privigen Liquid 10% (CSL Behring) | Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration | 4.6-5 | L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) | Ready-for use liquid 10% | <25 |
*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).
Immunosuppressive agents
Specific therapy for dermatitis and lymphadenitis involves immunosuppression with cyclosporine and the down-regulation of IL-4 and IL-5 with INF-g.
Cyclosporine (Sandimmune, Neoral)
Diarrhea and the youth of patients make high doses customary. Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and GVHD in various organs. Dose based on patient's ideal body weight.
Adult
Pediatric
15 mg/kg PO qd; monitor serum levels to maintain trough levels near 200 ng/mL
CYP3A4 inducers (eg, carbamazepine, phenytoin, isoniazid, rifampin, phenobarbital) may decrease concentrations; CYP3A4 inhibitors (eg, azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, clarithromycin) may increase toxicity; risk of acute renal failure, rhabdomyolysis, myositis, and myalgias increases with concurrent lovastatin
Documented hypersensitivity; uncontrolled hypertension or malignancies
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause hypertension, hirsutism, tremor, gingival hyperplasia, and headache; monitoring required for hypomagnesemia, hyperkalemia, hyperuricemia, nephrotoxicity, and hepatotoxicity
Interferons
These agents are naturally occurring cytokines that possess various biologic functions, including immunosuppressive action. They are produced by cells in response to viruses, double-stranded RNA, antigens, or mitogens, and they are classified in relation to biochemical properties and the cell of origin. These agents are commercially produced by means of recombinant DNA technology. Interferon gamma has been administered subcutaneously on a daily basis to interrupt processes mediated by IL-4 and IL-5 and to enhance a functional inflammatory response to infection.
Interferon gamma-1b (Actimmune)
Recombinant-derived cytokine possessing antiviral, immunomodulatory, and antiproliferative activity. Differs from interferon alfa and interferon beta by possessing significant antiproliferative activity. The immunomodulatory effects also differ, unlike interferon alfa or interferon beta; interferon gamma has potent macrophage activating effects.
Adult
Pediatric
<0.5 m2: 1.5 mcg/kg/dose SC (1 million IU = 50 mcg)
The issue of not using live virus vaccines with interferon because of potential immunosuppressive effect of interferon gamma is not relevant in Omenn syndrome; live virus vaccines are contraindicated because of the immunosuppressive nature of the disease, and fatal infections have occurred
Documented hypersensitivity or previous allergic reaction to products derived from Escherichia coli
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects less common in infants but include fever, chills, headache, myalgias, fatigue, and GI symptoms; caution in preexisting cardiac disease, seizure disorders, compromised CNS function, or myelosuppression
More on Omenn Syndrome |
| Overview: Omenn Syndrome |
| Differential Diagnoses & Workup: Omenn Syndrome |
 Treatment & Medication: Omenn Syndrome |
| Follow-up: Omenn Syndrome |
| Multimedia: Omenn Syndrome |
| References |
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References
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Further Reading
Keywords
Omenn syndrome, Omenn's syndrome, familial reticuloendotheliosis, severe combined immunodeficiency, SCID, erythroderma, desquamation, chronic diarrhea, failure to thrive, lymphadenopathy, hepatosplenomegaly, Pneumocystis carinii infections, Staphylococcus aureus sepsis, poliovirus, bone marrow transplantation, BMT, graft versus host disease, GVHD, pneumonia, poliomyelitis, eczema, alopecia
