Pediatric Complement Receptor Deficiency Treatment & Management
- Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD more...
Medical Care
In the severe phenotype of leukocyte adhesion deficiency (LAD) type 1, the prognosis for long-term survival is poor.[7] Immune reconstitution with hematopoietic stem cell transplantation is the treatment of choice.[23, 24, 25, 26] 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.[27] 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.[11] 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.[28]
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.
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.
Diet
In LAD type 1, no dietary restrictions are necessary. In LAD type 2, fucose dietary supplementation is indicated.
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| Receptor | Cluster Designation | Ligand | Cell Distribution | Activity |
| CR1 | CD35 | C3b/C4b | RBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cell | Immune adherence, phagocytosis |
| CR2 | CD21 | C3dg/C3d | B cell, follicular dendritic cell | Co-receptor for B-cell signaling |
| CR3 | CD11b/CD18 | C3bi, ICAM | Myeloid | Phagocytosis, immune adherence |
| CR4 | CD11c/CD18 | C3bi, ICAM | Myeloid | Phagocytosis, immune adherence |
| C1qRP | None | C1q, MBL, surfactant | Polymorphonuclear cell, macrophage | Promotes phagocytosis |
| C3aR | None | C3a, C4a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| C4aR | None | C4a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| C5aR | CD88 | C5a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin | ||||
| Disease | Inheritance | Genetic Defect | Protein Defect | Affected Cells | Affected Function | Manifestations |
| LAD type 1 | Autosomal recessive | INTGB2 | CD18 | Polymorphonuclear cell, macrophage, lymphocytes, NK cells | Tight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicity | Delayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation |
| LAD type 2 | Autosomal recessive | FUCT1 encoding for GDP-fucose transporter | Fucosylated proteins, sialyl-Lewis X (sLeX, CD15s) | Polymorphonuclear cell, macrophage | Rolling, chemotaxis, tethering | Same as LAD type 1 plus hh-blood group, mental retardation |
| LAD type 3 | Autosomal recessive | Kindlin 3 (FERMT3), involved in activation of integrin | Kindlin 3 | Polymorphonuclear cell, macrophage, lymphocytes, NK cells | Tight adherence | Same as LAD type 1 plus bleeding tendency |
| Rac 2 deficiency | Possibly autosomal dominant | RAC2 | Rac2, involved in regulation of actin cytoskeleton | Polymorphonuclear cell, decreased TRECs | Chemotaxis, O2- production | Recurrent infections, poor wound healing, leukocytosis, poor pus formation |
| E-selectin | Possibly autosomal recessive | Unknown | E-selectin | Endothelial cells | Rolling, tethering | Recurrent infections, poor pus formation, mild neutropenia |
| NK = Natural killer, TRECs = T-cell receptor excision circles | ||||||
| Molecule | CD Number | Distribution | Ligand | Function |
| Integrins | ||||
| LFA-1 | CD11a/CD18 | All leukocytes | ICAM-1, 2, 3 | Adhesion, migration |
| CR3 | CD11b/CD18 | Polymorphonuclear cell, macrophage, NK cells, eosinophils | ICAM-1,2; C3bi | Adhesion, migration |
| CR4 | CD11c/CD18 | All leukocytes | C3bi, ICAM-1, CD23, fibrinogen | Adhesion |
| Alpha4-beta7 | None | Lymphocytes, NK cells, eosinophils | MadCAM-1, VCAM-1, fibronectin | Adhesion, migration, rolling |
| VLA-4 | CD49d/CD29 | Lymphocytes, NK cells, eosinophils, basophils | VCAM-1, fibronectin | Adhesion, migration, rolling |
| Selectins | ||||
| E | CD62E | Endothelial cells, platelets | Sialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1 | Rolling |
| P | CD62P | Endothelial cells, platelets | Sialylated, fucosylated molecules (sLeX) expressed on PSGL-1 | No data |
| L | CD62L | Leukocytes | Sialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1 | Rolling |
| MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen | ||||
| Subtype | mRNA level | CD18 Expression | Clinical Presentation |
| 1 | None | None | Severe |
| 2 | Low | Trace | Moderate |
| 3 | Reference range | Trace, small protein precursor | Moderate |
| 4 | Reference range | Large protein precursor | Severe |
| 5 | Reference range | Normal protein precursor | Moderate |
| mRNA = messenger RNA. | |||
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