Pediatric Complement Receptor Deficiency 

Updated: Aug 06, 2019
Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

The complement system exerts many of its effects through complement receptors (CRs). Of the 8 plasma membrane receptors for complement, only deficiencies of CR3 and CR4 due to CD18 deficiency have been described, known as leukocyte adhesion deficiency (LAD) type 1.

Table 1. Complement Receptors (Open Table in a new window)

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

 

Diseases Related to the Complement System

CR1 (CD35)

Upon activation and cleavage of C3, C3b is formed as a major fragment that covalently binds to its target (see Table 1). C3b and C4b bind to CR1, which is present on various phagocytes and also on erythrocytes and B cells. CR1 participates in immune adherence and phagocytosis.[1] Immune adherence refers to the process by which bacteria coated with immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody and C3b adhere to erythrocytes, which facilitates phagocytosis by neutrophils. No complete congenital deficiency of CR1 has been reported. Acquired forms of CR1 deficiency have been associated with autoimmune disorders, such as systemic lupus erythematosus, hemodialysis in patients with diabetic nephropathy, and preeclampsia.[2] CR1 deficiency may partly account for the increased likelihood of infection reported in thesepatients.Recombinanterythropoietin(rEPO)hasbeenreportedtoincreaseerythrocyteCR1levels.

CR2 (CD21)

CR2 binds C3dg, and C3d is present on B cells and dendritic cells (see the Table 1). CR2 associates with CD19 forming a CR2-CD19 complex when stimulated by C3d-bearing antigen engaging CR2.[3] Thus, it enhances and prolongs antigen signaling on B cells.

Mutation of CR2 (CD21) has been associated with common variable immunodeficiency (CVID) characterized by onset of infections in early childhood. Serum IgG levels are decreased but serum IgA and IgM levels are normal; antibody responses to polysaccharide antigens are decreased and antibody responses to protein antigens are slightly reduced. B cells are normal but memory and switch B cells are low. Treatment is with intravenous or subcutaneous gammaglobulin treatment.[4]

C1q receptor for phagocytosis (C1qRP)

Evidence suggests that C1q binds a receptor present on phagocytic cells, termed C1qRP.[5] C1q is a member of the collectin family, which also includes surfactant A, surfactant D, and mannose-binding lectin (MBL). See Table 1. C1qRP binds to MBL and surfactants. Surfactants and MBL play an important role in innate immunity. MBL deficiency manifests as increased susceptibility to polysaccharide-encapsulated bacteria, with subsequent recurrent respiratory tract infections, abscesses, sepsis, and meningitis. C1qRP deficiency has not been described.

C3a, C4a, and C5a (CD88) receptors

Receptors for C3a and C5a have been identified; whether a distinct receptor for C4a is present is unclear (see Table 1). The C3a receptor binds C3a and C4a. These receptors are present on phagocytic cells, mast cells, and lung epithelial and smooth muscle cells.[6] These receptors play a role in C3a-mediated and C5a-mediated anaphylactic reactions.[7] Deficiencies of these receptors have not been described.

CR3 (CD11b/CD18) and CR4 (CD11c/CD18)

The CD11/CD18 complex is part of the beta-2 integrin family and is important in adhesion and phagocytosis (see Table 1).[8] Deficiency of CD18 on phagocytic cells causes LAD type 1 (see Table 2). Three CD11 alpha chains and a common CD18 beta chain form heterodimer transmembrane complexes (CD11a/CD18, CD11b/CD18, CD11c/CD18). See Table 3 below. CD11a/CD18 is also known as leukocyte factor antigen-1 (LFA-1), CD11b/CD18 is known as CR3, and CD11c/CD18 is known as CR4.

Ligands for CD11a/CD18 are intercellular adhesion molecules (ICAMs), ligands for CD11b/CD18 are complement C3bi and ICAMs, and ligands for CD11c/CD18 are C3bi and ICAMs. CD18 deficiency results in loss of expression of LFA-1, CR3 (CD11b/CD18), and CR4 (CD11c/CD18) (see Table 3). These defects lead to abnormal neutrophil, macrophage, and T-cell and B-cell adhesion to vascular endothelium and subsequent migration into infectious sites. In addition, T- and B-cell functions are severely decreased.

Table 2. Leukocyte Adhesion Defects (Open Table in a new window)

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

Table 3. Adhesion Molecules (Open Table in a new window)

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

 

Additional Leukocyte Adhesion Deficiency Syndromes

As seen in the image below, additional LAD syndromes have been identified that also interfere with the phagocytic cell adhesion cascade (see Table 2).[8]

LAD type 2 is due to decreased expression of fucosylated proteins, such as sialyl Lewis X (sLeX, CD15s), that are ligands for selectins necessary for the initiation of phagocytic cells attaching to endothelial cells in a process called rolling. LAD type 3 is due to defect of activation of Rap-1 important in the activation of integrins; this also results in defects of tight adherence. Rac2 deficiency results in decreased chemotaxis, superoxide anion production, and phagocytosis. E-selectin deficiency, a ligand for sialylated and fucosylated molecules, on endothelial cells results in decreased neutrophil rolling and tethering

LAD type 1, type 2, and type 3 are autosomal recessive disorders of neutrophils characterized by neutrophilia, recurrent severe bacterial infections, absence of inflammatory infiltrates, delayed umbilical-cord separation, and impaired wound healing (see Table 2). The defect in LAD type 1 is absent or defective expression of CD11/CD18 on the surface of neutrophils, macrophages, and lymphocytes.

Leukocyte adhesion deficiency type 1

Patients with LAD type 1 present either with a severe form with absence of CD18 or with a moderate form with 5–30% expression of CD18.[9, 10, 8] See Table 4. In the severe form, recurrent bacterial infections, skin infections, periodontitis, and gingivitis begin in the first year of life. Infections with Staphylococcus, Pseudomonas, Klebsiella, Enterococcus, and Proteus species and with Escherichia coli are common. Infectious sites are typically devoid of inflammatory cells because of the adhesion defect. Without immune reconstitution, death usually ensues when patients are younger than 2 years. In the moderate phenotype, the clinical course is much milder.

Table 4. Subtypes of Leukocyte Adhesion Deficiency Type 1 (Open Table in a new window)

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.

Leukocyte adhesion deficiency type 2

LAD type 2 deficiency is caused by defective fucosylation that leads to immunodeficiency and psychomotor retardation.[11, 12, 13, 14, 8] LAD type 2 is due to a defect in fucose metabolism that leads to deficiency of ligands for endothelial selectins, such as sLeX (CD15s), but normal expression of CD11/CD18 complexes (see Table 2). The defect leads to abnormal neutrophil rolling, although neutrophil adherence is normal (see Table 3). Also, T- and B-cell functions are normal.

LAD type 2 has been reported in approximately 4 families of Arabic origin. The clinical course is milder, characterized by severe periodontitis; however, severe infections are not usually observed (see Table 2). Other features of LAD type 2 include severe mental retardation, distinctive facies, and short stature. The facial features include a broad and depressed nasal bridge, long eyelashes, and a simian crease, and dorsally positioned second toes are present. In addition, neither the H blood group antigen (Bombay phenotype) nor the Lewis blood type antigens (Lea and Leb) are expressed.

The genetic defect is due to defective Golgi-GDP-fucose transporter (GFTP). GFTP serves to transport the nucleotide sugar GDP-fucose into the Golgi lumen, where the sugar serves as a substrate for fucosylation reactions mediated by several fucosyl transferases. GFTP is a 364 aa protein with 10 transmembrane domains with carboxy and amino termini exposed to the cytosol. The defect leads to decreased fucosylated carbohydrate molecules, such as leukocyte sialyl Lewisx (sLex), which severely decreases interactions with endothelial selectins. This reduces selectin-mediated leukocyte tethering and rolling.

The reason hypofucosylation leads to abnormal neurodevelopment is unknown. One speculation is that the cause is decreased signaling through Notch, which is required for a number of development processes. Four Notch proteins (Notch 1-4) have been reported. They are cell-surface molecules that are cleaved after binding to ligands (Delta 1, 3, and 4 and Jagged 1, and 2). Notch receptors are O-fucosylated and critical for Notch-ligand binding. The cleaved Notch is then translocated into the nucleus, where it activates several genes implicated in developmental processes. L-fucose supplementation is the recommended treatment for patients with LAD type 2 and does improve immunodeficiency.

Leukocyte adhesion deficiency type 3

LAD type 3 was described in 2 Arab brothers and 18 Turkish patients with profound leukocytosis, recurrent infections with absence of pus, and platelet aggregation defects resulting in bleeding (see Table 2).[15] The neutrophils demonstrated normal neutrophil rolling and opsonophagocytosis but abnormal neutrophil chemotaxis and tight adherence, similar to that found in LAD type 1 deficiency.

The genetic defect was identified as stop codon mutations in Kindlin3, also known as FERMT3.[15] Kindlin3 is expressed exclusively in hematopoietic cells. Kindlin3 plays an essential role in the proper conformation of integrins to active form. Integrin activation starts by chemokine induction through membrane bound G-protein coupled receptors (GPCR) and transduction by CalDAG GEF1 and Rap1 intracellularly. Rap1-GTP-interacting adapter molecule (RIAM) then binds activated Rap1 to Talin which leads to binding to the cytoplasmic tail of the β-integrin chain. Kindlin3 enables Talin to induce a modification of integrins from an inactive bent conformation to an active open conformation.

Leukocyte adhesion deficiency type 1/variant syndrome

LAD type 1/variant syndrome consists of a moderate LAD type 1–like syndrome and a severe Glanzmannlike bleeding disorder.[8, 16] Thus, it clinically resembles LAD type 3. LAD type 1/variant syndrome is rare and only a few patients, predominantly of Turkish descent, have been described. The clinical picture consists of delayed cord detachment; recurrent bacterial, fungal, and cytomegalovirus infection, beginning early in infancy; and poor wound healing. Bleeding tendency is moderate to severe, requiring repeated platelet transfusions. Neutrophilia is not as severe as seen in LAD type 1, with a WBC count of 10,000-30,000 with 60-90% neutrophils.

Mutations of FERMT3 have been found to be caused by truncation mutations of FERMT3 (Kindlin3).[17] Neutrophil adhesion, chemotaxis, and zymosan-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity are decreased. CD18 gene and protein expression are normal; Rap1, Rap2, and Rap regulatory activity are normal. GPCR-induced integrin activation is absent, similar to that seen in LAD type 3. Successful bone marrow transplantation has been performed in patients with LAD type 1/variant syndrome.

Rac2 deficiency

A male patient with a mutation of RAC2 was reported to be a cause of LAD.[18, 19] RAC2 is a member of the Rho family of guanosine triphosphatases (GTPases) critical in the regulation of the actin cytoskeleton and superoxide production. Upon clinical evaluation, the patient had profound leukocytosis, perirectal abscesses and poor wound healing with an absence of pus. Chemotaxis, superoxide anion production, phagocytosis, and neutrophil primary granule release were impaired. Accetta et al described a patient with markedly decreased TRECs identified on newborn screening who was subsequently diagnosed with Rac2 LAD.[20]  Bone marrow transplantation was performed resulting in clinical cure and correction of neutrophil defects.

E-selectin deficiency

Another molecular defect causing LAD was described in a female patient with defective endothelial expression of E-selectin.[21] She had Pseudomonas omphalitis, recurrent ear and urinary tract infections, and severe soft tissue infections with poor pus formation. She also had mild neutropenia, but the number of neutrophils increased in response to infection and infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF). Because of decreased E-selectin expression, defective rolling and tethering of phagocytic cells was suggested.[8]

Pathophysiology

The basis of LAD type 1 is various mutations in the common beta chain (CD18) of the beta-2 integrin family located on chromosome 21.[8, 22] Genes for the 3 CD11 chains (CD11a, CD11b, CD11c) are clustered on chromosome arm 16q. Defects in the beta chain result in the absence, insufficient amount, or abnormal function of the common CD18 unit. Two CD11 and 2 CD18 genes form the CD11/CD18 heterodimer complex. CD11/CD18 are members of the liver-cell adhesion molecule (LCAM) family, and their ligands are ICAMs and fibrinogen (see Table 3).

CD11a/CD18 is present on all leukocytes; CD11b/CD18 and CD11c/CD18 are present on neutrophils, macrophages, NK cells, and subsets of T cells and B cells (see Table 3). With these receptor-ligand interactions, these molecules play a crucial role in tight adhesion to endothelial vessel walls. In the initial adhesion step under conditions of blood flow, leukocytes begin a process of rolling. This is largely mediated by selectins, CD62E, CD62P, and CD62L, present on endothelial cells (see Table 3). Sialyl-Lewis X (sLeX, CD15s) is one of the counterligands. A defect in fucosylated proteins (eg, sLeX) that are ligands for selectins causes LAD type 2 and abnormal neutrophil rolling (see the image below). Absence of the neutrophil receptor for E-selectin (CD62E) results in a similar inability for neutrophils to migrate to inflammatory sites and respond to infections.

Protein defects. Protein defects.

In the next step, neutrophils firmly adhere to the endothelial vessel wall and then transmigrate (see the image above). CD18 defects cause a marked decrease in firm neutrophil adherence. In addition, transmigration of neutrophils is abnormal. As a result, in infectious sites, inflammatory cells are scarce. Also, CD11/CD18 is involved with T-cell and B-cell and macrophage interactions; therefore, CD18 defects lead to decreased T-cell function and decreased CD8, NK, and antibody-dependent cell-mediated cytotoxicity (ADCC).

The diversity of the gene defects causes 5 subtypes of LAD type 1 in which genotype produces different phenotype expression (see Table 4):

  • Type 1 LAD1 produces no beta subunit mRNA, produces no CD18, and produces severe clinical disease.

  • Type 2 LAD1 has low levels of mRNA, trace CD18, and moderate clinical disease.

  • Type 3 LAD1 has reference range levels of mRNA and a small protein precursor, and it produces moderate clinical disease. (Types 2 and 3 have approximately 3-10% expression of CD11/CD18.)

  • Type 4 LAD1 has reference range levels of mRNA and a large protein precursor, and it produces severe clinical disease.

  • Type 5 LAD1 has reference range mRNA levels and a normal protein precursor, and it produces moderate disease.

Heterozygotes have approximately one half of the normal amounts of CD11/CD18 on phagocytic cells and lymphocytes and have no clinical disease.

Epidemiology

Frequency

Leukocyte adhesion deficiency type 1 is estimated to occur in 1 per million people worldwide. At least 300 cases of this condition have been reported in the scientific literature.[23]

Demographics

LAD syndromes affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD I is by far the more common one with several hundreds of patients reported in the medical literature from all over the world. LAD II is very rare reported in less than 10 patients and LAD III is also rare with 25 patients mainly from the Middle East region. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population. LAD I was first described in the medical literature in 1979. LAD II was first reported in 1992. LAD III was first reported in 1997.[24]

The first clue to LAD type 1 may be the delayed separation of the umbilical cord. This is not manifested in LAD type 2. Patients with LAD type 1 with the severe phenotype are susceptible to infections beginning at birth and these infections typically occur by age 3–6 months. In LAD type 1 moderate phenotypes, infections are milder and may occur later.

Mortality/Morbidity

Five subtypes of LAD type 1 are recognized, with moderate-to-severe clinical phenotypes.[8] The severe phenotype of LAD type 1 is a life-threatening primary immunodeficiency with severe infections. A recent study noted that the incidence of primary immunodeficiencies markedly increased from 1976-2006.[25] Children rarely live past age 2 years without immune reconstitution. In the more mild-to-moderate phenotypes of LAD type 1, the clinical course is milder and the patients have a better prognosis. In both forms, wound healing is abnormal. Skin ulcers and/or necrotic lesions may form; skin grafts may be necessary. Abnormal dentition, with loss of deciduous and secondary teeth, occurs in all phenotypes of LAD.

LAD type 2 is associated with marked periodontitis.[8] Some patients with LAD type 2 have also had severe bacterial infections, similar to patients with LAD type1. In addition, patients with LAD type 2 often have short stature, delayed development, and mental retardation.

Prognosis

The prognosis of patients with the LAD type 1 severe phenotype is poor; these patients require immune reconstitution.

Patients with mild and moderate phenotypes of LAD type 1 have infections of decreased severity.

CD18 expression of 10% seems to confer protection against invasive life-threatening infections.[9]

 

Presentation

History

The 5 subtypes of leukocyte adhesion deficiency (LAD) 1 depend on the level of messenger RNA (mRNA) CD18 expression, the level of CD18 protein expression, and the clinical severity.[8] In subtypes 1 and 4 of LAD 1, there is absence of CD11/CD18 expression and patients have severe life-threatening infections (see Table 4). In subtypes 2, 3, and 5 of LAD type 1, diminished CD11/CD18 (3–10% of normal) is observed; however, the patients have less severe infections and chronic periodontitis. Initial reports described LAD as delayed separation of the umbilical cord (after 21 d or longer). Delayed separation of the umbilical cord is observed in the severe form of LAD type 1 but may not occur in the milder forms or in LAD type 2.

The hallmark of LAD type 1 is infection without pus and inflammatory response. The immune defect in LAD type 1 results in decreased neutrophil inflammatory responses and decreased cellular cytotoxicity. The types of infections and susceptibility to microorganisms resemble other neutrophil defects. Onset of infections somewhat varies. In the severe form of LAD type 1, infections often have an onset by age 3–4 months. In milder phenotypes of LAD type 1, onset of infections may be delayed. The most common infections in both phenotypes are otitis media, ulcerative stomatitis, gingivitis, periodontitis, and skin subcutaneous abscesses. Periodontitis and gingivitis are the principal infections observed in LAD type 2.

Guidelines for the diagnosis and management of primary immunodeficiencies have been established.[26]

  • Patients with LAD have the following types of infections:

    • Necrotic cutaneous abscesses and cellulitis

    • Mucosal and perirectal abscesses

    • Omphalitis

    • Periodontitis, leading to gingival hyperplasia and loss of alveolar bone and teeth

    • Gingivitis

    • Otitis media

    • Pneumonia

    • Peritonitis

    • Necrotizing enterocolitis

    • Intestinal ulceration

    • Aseptic meningitis

  • Patients with LAD are susceptible to a wide spectrum of gram-positive and gram-negative bacteria, most commonly Staphylococcus aureus, Pseudomonas species, enterobacteria, and Candida albicans.

  • In LAD type 2, other problems include severe mental retardation, short stature, and distinctive facial features. The facial features include long eyelashes and a broad and depressed nasal bridge.

  • In LAD type 3, the clinical manifestations are similar to that seen in LAD type 1, but there is also a bleeding tendency due to abnormal platelet aggregation.

  • In E-selectin deficiency, mild neutropenia is observed instead of the marked leukocytosis found in other types of LAD.

Physical

Physical examination findings are those of infections. Infectious sites are typically devoid of inflammatory cells. Signs of inflammation, such as erythema, are absent. In addition, pus is absent in infected drainages. Indolent and necrotic abscesses and cellulitis occur. Gingivitis and periodontitis occur in all the types of LAD. Another hallmark of LAD is poor wound healing. This may lead to the formation of a characteristic paper-thin bluish scar. Lymphoid tissue is normal in size.

Children with LAD type 2 have severe mental retardation, distinctive facies, and short-limbed dwarfism. The facial features include flat face, long eyelashes, broad and depressed nasal bridge, and anteverted nostrils. The palms of the hands are broad, dorsally positioned second toes were reported in one patient, and a simian crease may be present.

Causes

LAD type 1 is an autosomal recessive immunodeficiency disorder affecting the CD11/CD18 complex. Defects in the beta chain result in the absence, insufficient amount, or abnormal function of the common CD18 unit.

 

DDx

Diagnostic Considerations

The types of infections and infectious microorganisms that occur in leukocyte adhesion deficiency (LAD) type 1 resemble those that occur in patients with neutropenia. Other defects of neutrophils, such as chronic granulomatous disease (CGD) and hyperimmunoglobulin E (HIE) produce similar susceptibility to infections. However, in both CGD and HIE, lymphadenopathy and splenomegaly occur as well as neutrophil inflammatory response to infections.

Differential Diagnoses

 

Workup

Laboratory Studies

Extreme neutrophilia (>15,000/mcL) is a constant feature of leukocyte adhesion deficiency (LAD) type 1, type 2, type 3, and Rac2 deficiency because of inability of neutrophil margination.

  • The WBC count is 15-161 X 103/µL (15,000-161,000/mcL) with 50-90% neutrophils.

  • Neutrophilia is present in the absence of infections and increases with infections.

  • In E-selectin deficiency, mild neutropenia is present but increases with infections.

The diagnosis of LAD type 1 is confirmed by an absence of CD11a,b,c/CD18 on neutrophils, macrophages, and lymphocytes on flow cytometry.

  • In addition, neutrophil function is impaired, with abnormal adherence, chemotaxis phagocytosis, and deficient respiratory burst.

  • Numbers of T and B cells and their function are normal.

  • However, natural killer (NK)-cell and T-cell cytotoxicity is depressed.

  • Responses on mixed lymphocyte culture (MLC) may be markedly decreased.

  • CD15s expression is normal in LAD type 1.

In LAD type 2, CD15s (sLeX) expression is absent on neutrophils. CD11/CD18 expression is normal.

  • Neutrophil rolling is decreased but adhesion is normal.

  • Numbers and function of T and B cells are decreased.

  • Erythrocyte H antigens are absent, leading to expression of the Bombay (hh) phenotype. As a result, anti-H antibodies are present.

In examination of infections in children with LAD type 1, signs of inflammation, eg, erythema, pus formation, are decreased to absent.

  • Necrotic cutaneous, mucous membrane, and periodontal infections are the hallmark of LAD type 1.

  • In deep-seated infections, such as in the lungs and abdomen, the same process occurs.

  • Inflammatory infiltrations are decreased.

  • Therefore, findings on chest or abdominal radiography findings may lead to underestimates of the infectious process.

  • Imaging studies more sensitive than radiography, such as chest CT, may define the infectious process better than radiography.

  • Appropriate cultures are obtained from suspected infectious sites. Although inflammatory cells are decreased to absent, microorganisms can be identified.

Imaging Studies

No specific radiographic studies are necessary to make a diagnosis.

As previously discussed, imaging studies are useful in diagnosing infections.

Histologic Findings

The most striking finding in biopsies of infections in patients with all forms of LAD is the absence of neutrophils and other inflammatory cells.

 

Treatment

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.[27, 28, 29] {ref2733-INVALID REFERENCE} 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.[30] 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.[31, 32]

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.

Prevention

Education of the parents and patient for early recognition and need for early treatment of infections is essential.

Good oral hygiene is important to manage the oral infections (eg, gingivitis, periodontitis).

 

Medication

Medication Summary

Patients with leukocyte adhesion deficiency (LAD) type 1 are susceptible to various bacterial infections. To direct appropriate antibiotic therapy, obtaining cultures from infectious sites is essential. Infections with Staphylococcus, Pseudomonas, Klebsiella, and Enterococcus species and E coli are common. Therefore, antibiotic coverage of these organisms may be initiated until the specific organism is identified and sensitivity is completed.

Although some patients have been treated with prophylactic antibiotics, their use in LAD has not been demonstrated. Immunizations should be continued in these patients because antibody responses are present although abnormal.

 

Follow-up

Further Outpatient Care

Outpatient intravenous antibiotics, usually through a percutaneous line or central line, can be administered to treat infections.

Surgical treatment has been performed when necessary, and the organism has been identified.

Further Inpatient Care

Inpatient care is required to treat infections in patients with leukocyte adhesion deficiency (LAD), which is caused by complement receptor deficiency.

Patients with infections may need surgical drainage, debridement, and intravenous antibiotics.

 

Questions & Answers

Overview

What are complement receptors?

What is pediatric complement receptor 1 (CR1) deficiency?

What is pediatric complement receptor 2 (CR2) deficiency?

What is pediatric complement receptor C1qRP deficiency?

What are pediatric complement receptors C3a, C4a and C5a deficiencies?

What is pediatric complement receptor 3 (CR3) and 4 (CR4) deficiency?

What are leukocyte adhesion deficiency (LAD) syndromes?

What is leukocyte adhesion deficiency (LAD) type 1?

What is leukocyte adhesion deficiency (LAD) type 2?

What is leukocyte adhesion deficiency (LAD) type 3?

What is leukocyte adhesion deficiency (LAD) type 1/variant syndrome?

What is the role RAC2 in the etiology of leukocyte adhesion deficiency (LAD)?

What is the role of E-selectin in the etiology of leukocyte adhesion deficiency (LAD)?

What is the pathophysiology of leukocyte adhesion deficiency (LAD)?

What is the prevalence of leukocyte adhesion deficiency (LAD)syndrome?

At what age does leukocyte adhesion deficiency (LAD) syndrome typically present?

What is the mortality and morbidity associated with leukocyte adhesion deficiency (LAD) type 1?

What is the mortality and morbidity associated with leukocyte adhesion deficiency (LAD) type 2?

What is the prognosis of leukocyte adhesion deficiency (LAD) syndrome?

Presentation

Which clinical history findings are characteristic of leukocyte adhesion deficiency (LAD) syndrome?

Which physical findings are characteristic of leukocyte adhesion deficiency (LAD) syndrome?

What causes leukocyte adhesion deficiency (LAD) syndrome?

DDX

Which conditions are included in the differential diagnoses of leukocyte adhesion deficiency (LAD) syndrome?

What are the differential diagnoses for Pediatric Complement Receptor Deficiency?

Workup

What is the role of lab tests in the workup of leukocyte adhesion deficiency (LAD) syndrome?

How is a diagnosis of leukocyte adhesion deficiency (LAD) type 1 confirmed?

Which lab findings are characteristic of leukocyte adhesion deficiency (LAD) type 2?

Which tests are performed in the workup of leukocyte adhesion deficiency (LAD) type 1?

What is the role of imaging studies in the workup of leukocyte adhesion deficiency (LAD) syndrome?

Which histologic findings are characteristic of leukocyte adhesion deficiency (LAD) syndrome?

Treatment

How is leukocyte adhesion deficiency (LAD) type 2 treated?

How is leukocyte adhesion deficiency (LAD) type 3 treated?

How is leukocyte adhesion deficiency (LAD) type 1 treated?

What is the role of surgery in the treatment of leukocyte adhesion deficiency (LAD) syndrome?

Which specialist consultations are beneficial to patients with leukocyte adhesion deficiency (LAD) syndrome?

Which dietary modifications are used in the treatment of leukocyte adhesion deficiency (LAD) syndrome?

What is included in patient education about leukocyte adhesion deficiency (LAD) syndrome?

Medications

What is the role of medications in the treatment of leukocyte adhesion deficiency (LAD) syndrome?

Follow-up

What is included in the outpatient management of infections in leukocyte adhesion deficiency (LAD) syndrome?

When is surgery indicated in the treatment of leukocyte adhesion deficiency (LAD) syndrome?

When is inpatient care indicated for the treatment of leukocyte adhesion deficiency (LAD) syndrome?