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Pediatric Wiskott-Aldrich Syndrome Medication

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Jul 15, 2016
 

Medication Summary

Otitis media is treated with conventional first-line antibiotics (eg, amoxicillin, amoxicillin/clavulanate, cefuroxime axetil). Intramuscular injection of antibiotics is avoided because of the risk of excessive bleeding. The duration of antibiotic therapy should follow conventional recommendations for the specific infection being treated.

Most medical care is provided on an outpatient basis with the caveat that episodes of bacteremia and sepsis present higher risks for patients with Wiskott-Aldrich syndrome (WAS), and signs and symptoms may be subtle because of an inadequate inflammatory response resulting from phagocytic and humoral immune defects.

Administration of tetanus and diphtheria toxoids and the acellular pertussis and conjugated Hib and pneumococcal vaccines is essential and usually results in a protective, although subnormal, antibody response. The attenuated varicella vaccine has been administered without complication. Live measles and poliovirus vaccines are contraindicated. Influenza and hepatitis vaccines should be safe, but experience in administering them to patients with Wiskott-Aldrich syndrome is limited.

IVIG has been administered to selected patients with frequent bacterial infections.

Some patients may benefit from conventional inhaler therapies for reactive airway disease.

Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

The consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400-600 mg/kg/mo or a dose that maintains trough serum immunoglobulin G (IgG) levels greater than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages 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 are noted (eg, solvent detergent versus pasteurization and liquid versus lyophilized). The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences.

Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, age >65 y, use of nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

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 those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving reference range serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much 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 or patients with active infections have more severe reactions.

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 Fc receptors and 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 per dose), diphenhydramine (1 mg/kg per dose), and/or hydrocortisone (6 mg/kg per dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using 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 sucrose per kg/min. 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 BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in IgA-deficient patients. A few reports suggest true anaphylaxis 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 very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (XLA) (Bruton disease) or severe combined immunodeficiency (SCID). Exercise caution in patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the Table below).

Table. Immune Globulin, Intravenous[37, 38, 39, 40] (Open Table in a new window)

Brand(Manufacturer) Manufacturing Process pH Additives (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].) 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
Gammaplex



(Bio Products)



Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation 4.8-5.1 Contains sorbitol (40 mg/mL); do not administer if fructose intolerant Ready-for-use solution 5% < 10
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)



9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events



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 (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) Ready-for-use liquid 10% ≤ 25
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Antibiotics

Class Summary

Amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil are the PO drugs of choice for the common extracellular bacteria that cause sinopulmonary infections. Ceftriaxone administered intravenously is the first-line antibiotic for suspected bacteremia or sepsis and for pneumonia. It covers penicillin-resistant pneumococci. Intramuscular administration is avoided because of bleeding caused by thrombocytopenia. Nafcillin is chosen for invasive S aureus. Vancomycin is needed for penicillin-allergic patients and for treatment of methicillin-resistant S aureus. Vancomycin-resistant S aureus, GISA, may require fluoroquinolones, linezolid or Synercid.

Prophylactic antibiotics for patients with splenectomies are penicillin or amoxicillin; a macrolide can be used for penicillin-allergic patients.

Amoxicillin (Trimox, Amoxil, Biomox)

 

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin/clavulanate (Augmentin)

 

Drug combination treats bacteria resistant to beta-lactam antibiotics.

For children >3 mo, base dosing protocol on amoxicillin content. Because of different amoxicillin–clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Cefuroxime axetil (Ceftin)

 

Second-generation cephalosporin maintains gram-positive activity that first-generation cephalosporins have. Adds activity against Proteus mirabilis, H influenzae, E coli, K pneumoniae, and Moraxella catarrhalis.

Ceftriaxone (Rocephin)

 

Third-generation cephalosporin with broad-spectrum activity; efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.

Vancomycin (Lyphocin, Vancocin, Vancoled)

 

Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Indicated for patients who cannot receive or who have not responded to penicillins and cephalosporins or who have infections with resistant staphylococci.

To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h before next dosing. Use creatinine clearance to adjust dose in patients with renal impairment.

Nafcillin

 

DOC for acute pneumonia and deep-seated abscesses caused by S aureus.

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Bronchodilators, Inhaled

Class Summary

These agents are used to relieve bronchoconstriction and decrease the inflammatory response in the respiratory tree. Both pulmonary and nasal inhalers may be needed. Children 4 years and older may use inhalers effectively. Inhaler use is hampered in young children and others unable to understand the technique of administration and in older individuals unable to achieve a forceful inhalation. Adding a spacer is customary to improve coordination in children. Steroid inhalation is followed by rinsing the mouth to avoid thrush, and a spacer is highly recommended for use with steroid pressurized metered dose inhalers for all patients.

Albuterol (Proventil HFA, Ventolin HFA)

 

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Salmeterol (Serevent Diskus)

 

By relaxing the smooth muscle fibers of the bronchioles it can relieve bronchospasms. Effect may also facilitate expectoration.

Beclomethasone (QVAR)

 

Inhibits bronchoconstriction mechanisms and produces direct smooth muscle relaxation. May decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Some patients may require higher doses of inhaled beclomethasone. Available as 40-mcg and 80-mcg per inhalation.

Fluticasone (Flovent HFA)

 

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically.

Some patients may require higher doses of inhaled fluticasone.

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Hyperimmune Globulins

Class Summary

A limited number of immunoglobulin preparations have been developed to provide prophylaxis against specific microorganisms. For primary immunodeficiency diseases including Wiskott-Aldrich syndrome, VZIG has proven efficacy to prevent primary varicella when administered within 48-72 hours postexposure. It may modify varicella when administered up to 96 hours later.

Varicella-zoster immune globulin (VariZIG)

 

Contains IgG varicella-zoster antibodies. Provides passive immunization to exposed individuals at high risk of complications from varicella. Administration recommended within 48 h postexposure but may be efficacious up to 96 h postexposure. The US product VZIG was discontinued by the manufacturer. An investigational product (VariZIG) is currently available via IND (contact FFF Enterprises at 800-843-7477).

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Immunizations

Class Summary

Vaccines that contain viral components (not live viruses) should be administered to patients with Wiskott-Aldrich syndrome because a protective antibody response is often obtained. Injection technique is critical because of the risk of bleeding and hematoma at the injection site. Live virus vaccines are contraindicated with the possible exception of varicella-zoster virus. For current Advisory Committee on Immunization Practices (ACIP) recommended immunizations schedule for immunocompromised individuals, see the Centers for Disease Control and Prevention (CDC) guidelines.[41, 42]

Vaccines

 

Diphtheria and tetanus toxoids (DT or Td), acellular pertussis, conjugated HIB, conjugated pneumococcal vaccine, unconjugated meningococcal A and C, hepatitis B (HBV), and influenza. CDC/AAP recommendations undergo continuing reevaluation.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Robyn Siperstein, MD Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School

Robyn Siperstein, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for MOHS Surgery, Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD 

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Additional Contributors

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

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  61. Tsuji Y, Imai K, Kajiwara M, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006 Mar. 37(5):469-77. [Medline].

  62. Wietstruck PMA, Zuniga CP, Talesnik GE, Mendez RC, Barriga CF. [Hematopoietic stem cell transplantation for patients with Wiskott-Aldrich syndrome]. Rev Med Chil. 2007 Jul. 135(7):917-23. [Medline].

  63. Xie JW, Zhang ZY, Wu JF, Liu DW, Liu W, Zhao Y, et al. In vivo reversion of an inherited mutation in a Chinese patient with Wiskott-Aldrich syndrome. Hum Immunol. 2015 Apr 8. [Medline].

 
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This 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.
This 1-year-old boy was hospitalized because of respiratory syncytial virus bronchiolitis but was noted to have eczema and petechiae (note arrow). His history was significant for a subdural hematoma for which trauma was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser).
Table. Immune Globulin, Intravenous [37, 38, 39, 40]
Brand(Manufacturer) Manufacturing Process pH Additives (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].) 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
Gammaplex



(Bio Products)



Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation 4.8-5.1 Contains sorbitol (40 mg/mL); do not administer if fructose intolerant Ready-for-use solution 5% < 10
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)



9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events



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 (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) Ready-for-use liquid 10% ≤ 25
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