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Pediatric Complement Receptor Deficiency Treatment & Management

  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Feb 11, 2013
 

Medical Care

In the severe phenotype of leukocyte adhesion deficiency (LAD) type 1, the prognosis for long-term survival is poor.[8] Immune reconstitution with hematopoietic stem cell transplantation is the treatment of choice.[24, 25, 26, 27] Numerous stem cell donor choices, human leukocyte antigen (HLA)–matched related bone marrow, HLA-matched cord blood, and HLA-matched unrelated bone marrow, have been successfully used to immune reconstitute patients with LAD type 1. Preexisting infections, which are common, must be successfully treated before transplantation. Patients with preexisting infections may need surgical drainage, debridement, and intravenous antibiotics.

The bone marrow in patients with LAD is hyperplastic, and some T-cell function is present. Therefore, myeloablative treatment to make room in the bone marrow and immunosuppressive therapy to prevent graft rejection has been used. The absence of LFA-1 on host's cells that cause decreased T-cell function, T-cell cytotoxicity, and natural killer (NK) cell cytotoxicity may actually facilitate engraftment. Both acute and chronic graft versus host disease (GVHD) have been a problem in patients with LAD even when an HLA-matched sibling donor is used.

  • Treatment of infections in patients with the severe phenotype of LAD type 1 can be difficult.
    • Treatment often requires appropriate intravenous antibiotics.
    • Surgical drainage of abscesses and surgical debridement of infected necrotic tissue is often required.
    • Some patients have undergone amputation of limbs to control infected bone.
    • The gingivitis and periodontitis that occurs in all forms of LAD often requires surgery, sometimes with removal of dentition.
    • Because of poor wound healing, complications such as fistulas may occur. Therefore, surgical care is complex as well.
    • Infections in patients with the moderate phenotype of LAD type 1 can often be treated with oral antibiotics.
    • Mellouli et al reported successful granulocyte transfusions in a patient with LAD1 who had Fusariumsolani ecthyma gangrenosum.[28] The patient had received antifungal and antibacterial therapy, which did not clear his infections. Then the patient received irradiated phenotyped granulocyte transfusions along with G-CSF and continued antifungal therapy over 5 months. This resolved the infection.
  • LAD type 2 is a metabolic defect of fucose metabolism that affects all fucosylated molecules, including sialyl-Lewis X, which is deficient in LAD type 2.
    • The biochemical activity of GDP-D-mannose-4,6 dehydratase (GMD) that converts mannose to fucose is decreased in patients with LAD type 2. However, the primary defect is thought to be a GMD-regulating protein.
    • Erythrocyte fucosylated H antigens are also absent in LAD type 2 (Bombay phenotype).
  • Oral fucose supplementation has been successful in the treatment of patients with LAD type 2, with correction of expression CD15s on neutrophils.[12] Elevated neutrophil cell counts returned to the reference range, and clinical improvement was achieved with reduction of infections.
    • Patients with LAD type 2 were treated with 5 doses of fucose per day, starting at 25 mg/kg, which was slowly increased to 492 mg/kg.
    • After 40 days of fucose 140 mg/kg, levels of E-selectins, P-selectins, and CD15s reached approximately 50% the reference range.
    • Neutrophil counts decreased to the reference range.
    • H antigens on erythrocytes did not reappear.
    • Of importance, psychomotor development may also improve.
  • Treatment of LAD type 3 can be difficult. Because of the thrombocytopenia and bleeding problems, these patients require frequent transfusions. The only possible curable therapy is bone marrow transplantation, which so far has not been very encouraging.[29]
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Surgical Care

Consultation with an oral surgeon is necessary for most patients with any form of LAD. Consultation with a surgeon for surgical drainage and necrotic tissue debridement is ordered as indicated for patients with LAD.

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Consultations

Diagnosis and management of LAD should be referred to a hematologist and/or an immunologist. A hematologist or an immunologist skilled in bone marrow transplantation should perform this procedure.

Consultation with an oral surgeon is necessary for most patients with any form of LAD. Consultations to obtain appropriate cultures are often needed. This may include a pulmonologist to perform bronchoalveolar lavage (BAL), a surgeon to perform abscess aspirates, and an otolaryngologist to perform myringotomy or sinus aspirates. Consultation with an infectious diseases specialist may be indicated to select appropriate antibiotic coverage.

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Diet

In LAD type 1, no dietary restrictions are necessary. In LAD type 2, fucose dietary supplementation is indicated.

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Activity

Activity is not restricted.

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Contributor Information and Disclosures
Author

Alan P Knutsen, MD Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director Jeffrey Modell Diagnostic & Research Center for Primary Immuodeficiences (CGCMC), Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, Clinical Immunology Society

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.

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.

Acknowledgements

John Wilson Georgitis, MD Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, 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 College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

References
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Protein defects.
Table 1. Complement Receptors
ReceptorCluster DesignationLigandCell DistributionActivity
CR1CD35C3b/C4bRBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cellImmune adherence, phagocytosis
CR2CD21C3dg/C3dB cell, follicular dendritic cellCo-receptor for B-cell signaling
CR3CD11b/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
CR4CD11c/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
C1qRPNoneC1q, MBL, surfactantPolymorphonuclear cell, macrophagePromotes phagocytosis
C3aRNoneC3a, C4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C4aRNoneC4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C5aRCD88C5aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin
Table 2. Leukocyte Adhesion Defects
DiseaseInheritanceGenetic DefectProtein DefectAffected CellsAffected FunctionManifestations
LAD type 1Autosomal recessiveINTGB2CD18Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicityDelayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation
LAD type 2Autosomal recessiveFUCT1 encoding for GDP-fucose transporterFucosylated proteins, sialyl-Lewis X (sLeX, CD15s)Polymorphonuclear cell, macrophageRolling, chemotaxis, tetheringSame as LAD type 1 plus hh-blood group, mental retardation
LAD type 3Autosomal recessiveKindlin 3 (FERMT3), involved in activation of integrinKindlin 3Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherenceSame as LAD type 1 plus bleeding tendency
Rac 2 deficiencyPossibly autosomal dominantRAC2Rac2, involved in regulation of actin cytoskeletonPolymorphonuclear cell, decreased TRECsChemotaxis, O2- productionRecurrent infections, poor wound healing, leukocytosis, poor pus formation
E-selectinPossibly autosomal recessiveUnknownE-selectinEndothelial cellsRolling, tetheringRecurrent infections, poor pus formation, mild neutropenia
NK = Natural killer, TRECs = T-cell receptor excision circles
Table 3. Adhesion Molecules
MoleculeCD NumberDistributionLigandFunction
Integrins
LFA-1CD11a/CD18All leukocytesICAM-1, 2, 3Adhesion, migration
CR3CD11b/CD18Polymorphonuclear cell, macrophage, NK cells, eosinophilsICAM-1,2; C3biAdhesion, migration
CR4CD11c/CD18All leukocytesC3bi, ICAM-1, CD23, fibrinogenAdhesion
Alpha4-beta7NoneLymphocytes, NK cells, eosinophilsMadCAM-1, VCAM-1, fibronectinAdhesion, migration, rolling
VLA-4CD49d/CD29Lymphocytes, NK cells, eosinophils, basophilsVCAM-1, fibronectinAdhesion, migration, rolling
Selectins
ECD62EEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1Rolling
PCD62PEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX) expressed on PSGL-1No data
LCD62LLeukocytesSialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1Rolling
MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen
Table 4. Subtypes of Leukocyte Adhesion Deficiency Type 1
SubtypemRNA levelCD18 ExpressionClinical Presentation
1NoneNoneSevere
2LowTraceModerate
3Reference rangeTrace, small protein precursorModerate
4Reference rangeLarge protein precursorSevere
5Reference rangeNormal protein precursorModerate
mRNA = messenger RNA.
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