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Mannose-Binding Lectin Deficiency in a Child with Recurrent Infections
Mannose-Binding Lectin Deficiency in a Child with Recurrent Infections HEIDI E. MARTINSON, MD,
AND
FRANK T. SAULSBURY, MD
We describe an 11monthold girl with mannose-binding lectin deficiency who presented with recurrent infections. Her mother and brother also were affected. Mannose-binding deficiency is common, and we suggest that testing for it should be included in the evaluation of children with increased susceptibility to infection. (J Pediatr 2009;154:450-1)
he innate immune system is rapidly activated after an infectious challenge, and it provides the first line of immunologic defense against infection. Activation of the innate immune system relies on a large number of plasma proteins and cellular receptors that recognize conserved microbial structures termed pathogen-associated molecular patterns.1 These include carbohydrates, proteins, lipids, and nucleic acid motifs that are unique to microbial pathogens. In addition to providing the initial defense against infection, signals from the innate immune system are required to activate T-lymphocytes and B-lymphocytes of the adaptive immune system.1 Mannose-binding lectin (MBL) is an important component of the innate immune system, and MBL deficiency is associated with increased susceptibility to infection.2-5 MBL deficiency is quite common; it occurs in 5% to 8% of the population.6,7 This report describes an 11 month old child with MBL deficiency to alert pediatricians to this disorder.
T
CASE REPORT An 11 month old girl presented with a life-long history of increased susceptibility to infection. At 2 weeks of age she had bronchiolitis and acute otitis media. She had subsequent development of recurrent otitis media. Tympanostomy tubes were inserted when she was 6 months old, but she continued to have recurrent otitis media. She also had 1 episode of pneumonia and 1 episode of periorbital cellulitis. She did not have a history of septicemia or meningitis, skin or soft tissue abscesses, or infections with opportunistic organisms. Growth and development were normal. Family history revealed that her 3 year old brother also had recurrent otitis media. Her 32 year old mother had recurrent otitis media as a child, and she has recurrent sinusitis as an adult. The patient’s father is healthy, and he has no history of recurrent infections as a child or adult. Physical examination at 11 months of age showed a healthy-appearing girl, with height and weight in the normal range. Her examination result was normal except for bilateral tympanostomy tubes. Laboratory studies showed a white blood cell count of 9400/mm3 with 32% neutrophils, 60% lymphocytes, and 6% monocytes. The hemoglobin concentration was 11.7 g/dL and the platelet count was 639 000/mm3. The sweat chloride concentration was 16 meq/L. Serum immunoglobulin concentrations were normal for age with an immunoglobulin (IG) G level of 519 mg/dL, IgA of 54 mg/dL, IgM of 118 mg/dL, and IgE of 7 IU/mL. IgG antibody to tetanus toxoid was 0.75 IU/mL (nl ⬎ 0.15 IU/mL). The total hemolytic complement level was normal at 233 IU/mL (nl 101-300 From the Augusta Pediatrics, Fishersville IU/mL). Analysis of peripheral blood lymphocyte populations revealed normal propor(H.M.), and the Department of Pediatrics, University of Virginia Health System, Chartions of CD19, CD3, CD4, CD8, and CD16 cells. The serum MBL concentration was lottesville, VA (F.S.). ⬍0.5 ng/mL (nl ⬎ 100 ng/mL). The patient’s 3 year old brother and her mother were The authors have no real or potential contested, and both were found to have mannose binding lectin deficiency with levels of 35 flicts of interest. ng/mL and 2 ng/mL, respectively. The father was not tested. Submitted for publication Jun 12, 2008; last
DISCUSSION MBL is an important component of the innate immune system. It binds to a variety of carbohydrate groups, particularly mannose and N-acetylglucosamine, that are expressed on many microorganisms ranging from yeast to bacteria, viruses, and parasites.2 MBL
MBL
450
Mannose-binding lectin
revision received Aug 6, 2008; accepted Sep 4, 2008. Reprint requests: Frank T. Saulsbury, MD, Division of Immunology and Rheumatology, Department of Pediatrics, Box 800386, University of Virginia Health System, Charlottesville, VA 22908. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.09.016
promotes opsonization and elimination of pathogens via interaction with receptors on phagocytes.2 In addition, MBL provides a third pathway of complement activation. On binding to the relevant carbohydrate moiety, MBL is associated with an MBL-associated serine protease, which is capable of activating C4 and C2 of the classical complement pathway in the absence of antibody. Opsonic C3b is then generated promoting the ingestion and killing of the microorganisms.2 MBL is present in the serum at birth, and adult levels are reached by several weeks of life.8 MBL has a molecular weight of 400-700 kDa based on oligomerization of triple helix complexes, each of which is approximately 32 kDa.2 Serum MBL concentrations are genetically determined. Three structural mutations of codons 52, 54, and 57 in exon 1 of the MBL gene disrupt the assembly of the protein and lead to decreased MBL levels. In addition, 3 common polymorphisms in the promoter region affect MBL concentrations, but most clinically significant MBL deficiencies are associated with structural mutations.2 MBL deficiency caused by structural mutations is inherited in an autosomal dominant fashion.2-9 This is due to the fact that a single structural mutation will disrupt the assembly of the triple helix and subsequent oligomerization. Mutations in the MBL gene are common and 5-8% of individuals have very low or absent MBL serum levels.6,7 MBL deficiency is far more common than defects in the adaptive immune system. For example, IgA deficiency, the most prevalent immunodeficiency of the adaptive immune system occurs in 1:600 individuals, and common variable immunodeficiency is estimated to affect 1:25 000 individuals.10 Thus MBL deficiency is 30 times more common than IgA deficiency and 1000 times more common than common variable immunodeficiency. As a component of the innate immune system, MBL is particularly important in the defense against infection in immunologically naive hosts. In a prospective, cohort study, Koch et al5 showed that children with MBL deficiency had an increased risk of acute respiratory tract infections. However, the major risk was largely confined to children 6 to 17 months of age. The risk of infection was slightly increased in children 0 to 5 months of age, and MBL deficiency was not associated with an increased risk of infection in children 18 to 23 months of age. However, other studies suggest that the risk of infection associated with MBL deficiency persists throughout childhood.3,4 MBL deficiency is also associated with serious, life-threatening infections in children. Frakking et al11 reported that MBL deficiency was associated with an increased risk of early-onset sepsis and pneumonia in neonates. Hibberd et al12 reported that MBL deficiency is associated with an increased risk of meningococcemia and meningitis in children, and it may account for one third of all cases. MBL deficiency should be suspected in children with recurrent otitis media requiring the placement of tympanos-
Mannose-Binding Lectin Deficiency in a Child with Recurrent Infections
tomy tubes or adenoidectomy; recurrent sinusitis; recurrent lower respiratory tract infection; and serious, life-threatening infections. The diagnosis of MBL deficiency is straightforward. The measurement of serum MBL concentration is available at a number of commercial reference laboratories that are used commonly by many health care facilities. Replacement therapy with purified or recombinant MBL is feasible, and it is currently being studied, but there is no information at this time concerning efficacy. Our unpublished experience suggests that prophylactic antibiotic administration may decrease the frequency and severity of infections in children with MBL deficiency. The ultimate prognosis of MBL deficiency appears to be good. An increased risk of serious infections has been reported in adults with MBL deficiency.7,13 However, in a large population-based study, Dahl et al14 found no difference in infections or mortality rates in adults with MBL deficiency compared with control subjects. In summary, MBL deficiency is common. We suggest that measuring MBL levels should be a part of the evaluation of children with increased susceptibility to infection and suspected immunodeficiency.
REFERENCES 1. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007;449:819-26. 2. Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today 1996;17:532-40. 3. Garred P, Masden HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding protein alleles in patients with suspected immunodeficiency. Lancet 1995;346:941-3. 4. Summerfield JA, Sumiya M, Levin M, Turner MW. Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ 1997;314:1229-32. 5. Koch A, Melbye M, Sorensen P, Homoe P, Madsen HO, Molbak K, et al. Acute respiratory track infections and mannose-binding lectin insufficiency during early childhood. JAMA 2001;285:1316-21. 6. Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan-binding protein with a common defect of opsonization. Lancet 1989;2:1236-9. 7. Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infection. Clin Infect Dis 2003;37:1496-505. 8. Aittoniemi J, Miettinen A, Laippala P, Isolauri E, Viikari J, Ruuska T, et al. Age-dependent variation in the serum concentration of mannan-binding protein. Acta Paediatr 1996;85:906-9. 9. Sumiya M, Super M, Tabona P, Levinsky RJ, Arai T, Turner MW, et al. Molecular basis of opsonic defect in immunodeficient children. Lancet 1991;337: 1569-70. 10. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 2000;120:225-31. 11. Frakking FNJ, Brouwer N, van Eijkelenburg NKA, Merkus MP, Kuijpers TW, Offringa M, et al. Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. Clin Exp Immunol 2007;150:255-62. 12. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999;353:1049-53. 13. Summerfield JA, Ryder S, Sumiya M, Thursz M, Gorchein A, Monteil MA, et al. Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet 1995;345:886-9. 14. Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med 2004;199:1391-9.
451
AND
FRANK T. SAULSBURY, MD
We describe an 11monthold girl with mannose-binding lectin deficiency who presented with recurrent infections. Her mother and brother also were affected. Mannose-binding deficiency is common, and we suggest that testing for it should be included in the evaluation of children with increased susceptibility to infection. (J Pediatr 2009;154:450-1)
he innate immune system is rapidly activated after an infectious challenge, and it provides the first line of immunologic defense against infection. Activation of the innate immune system relies on a large number of plasma proteins and cellular receptors that recognize conserved microbial structures termed pathogen-associated molecular patterns.1 These include carbohydrates, proteins, lipids, and nucleic acid motifs that are unique to microbial pathogens. In addition to providing the initial defense against infection, signals from the innate immune system are required to activate T-lymphocytes and B-lymphocytes of the adaptive immune system.1 Mannose-binding lectin (MBL) is an important component of the innate immune system, and MBL deficiency is associated with increased susceptibility to infection.2-5 MBL deficiency is quite common; it occurs in 5% to 8% of the population.6,7 This report describes an 11 month old child with MBL deficiency to alert pediatricians to this disorder.
T
CASE REPORT An 11 month old girl presented with a life-long history of increased susceptibility to infection. At 2 weeks of age she had bronchiolitis and acute otitis media. She had subsequent development of recurrent otitis media. Tympanostomy tubes were inserted when she was 6 months old, but she continued to have recurrent otitis media. She also had 1 episode of pneumonia and 1 episode of periorbital cellulitis. She did not have a history of septicemia or meningitis, skin or soft tissue abscesses, or infections with opportunistic organisms. Growth and development were normal. Family history revealed that her 3 year old brother also had recurrent otitis media. Her 32 year old mother had recurrent otitis media as a child, and she has recurrent sinusitis as an adult. The patient’s father is healthy, and he has no history of recurrent infections as a child or adult. Physical examination at 11 months of age showed a healthy-appearing girl, with height and weight in the normal range. Her examination result was normal except for bilateral tympanostomy tubes. Laboratory studies showed a white blood cell count of 9400/mm3 with 32% neutrophils, 60% lymphocytes, and 6% monocytes. The hemoglobin concentration was 11.7 g/dL and the platelet count was 639 000/mm3. The sweat chloride concentration was 16 meq/L. Serum immunoglobulin concentrations were normal for age with an immunoglobulin (IG) G level of 519 mg/dL, IgA of 54 mg/dL, IgM of 118 mg/dL, and IgE of 7 IU/mL. IgG antibody to tetanus toxoid was 0.75 IU/mL (nl ⬎ 0.15 IU/mL). The total hemolytic complement level was normal at 233 IU/mL (nl 101-300 From the Augusta Pediatrics, Fishersville IU/mL). Analysis of peripheral blood lymphocyte populations revealed normal propor(H.M.), and the Department of Pediatrics, University of Virginia Health System, Chartions of CD19, CD3, CD4, CD8, and CD16 cells. The serum MBL concentration was lottesville, VA (F.S.). ⬍0.5 ng/mL (nl ⬎ 100 ng/mL). The patient’s 3 year old brother and her mother were The authors have no real or potential contested, and both were found to have mannose binding lectin deficiency with levels of 35 flicts of interest. ng/mL and 2 ng/mL, respectively. The father was not tested. Submitted for publication Jun 12, 2008; last
DISCUSSION MBL is an important component of the innate immune system. It binds to a variety of carbohydrate groups, particularly mannose and N-acetylglucosamine, that are expressed on many microorganisms ranging from yeast to bacteria, viruses, and parasites.2 MBL
MBL
450
Mannose-binding lectin
revision received Aug 6, 2008; accepted Sep 4, 2008. Reprint requests: Frank T. Saulsbury, MD, Division of Immunology and Rheumatology, Department of Pediatrics, Box 800386, University of Virginia Health System, Charlottesville, VA 22908. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.09.016
promotes opsonization and elimination of pathogens via interaction with receptors on phagocytes.2 In addition, MBL provides a third pathway of complement activation. On binding to the relevant carbohydrate moiety, MBL is associated with an MBL-associated serine protease, which is capable of activating C4 and C2 of the classical complement pathway in the absence of antibody. Opsonic C3b is then generated promoting the ingestion and killing of the microorganisms.2 MBL is present in the serum at birth, and adult levels are reached by several weeks of life.8 MBL has a molecular weight of 400-700 kDa based on oligomerization of triple helix complexes, each of which is approximately 32 kDa.2 Serum MBL concentrations are genetically determined. Three structural mutations of codons 52, 54, and 57 in exon 1 of the MBL gene disrupt the assembly of the protein and lead to decreased MBL levels. In addition, 3 common polymorphisms in the promoter region affect MBL concentrations, but most clinically significant MBL deficiencies are associated with structural mutations.2 MBL deficiency caused by structural mutations is inherited in an autosomal dominant fashion.2-9 This is due to the fact that a single structural mutation will disrupt the assembly of the triple helix and subsequent oligomerization. Mutations in the MBL gene are common and 5-8% of individuals have very low or absent MBL serum levels.6,7 MBL deficiency is far more common than defects in the adaptive immune system. For example, IgA deficiency, the most prevalent immunodeficiency of the adaptive immune system occurs in 1:600 individuals, and common variable immunodeficiency is estimated to affect 1:25 000 individuals.10 Thus MBL deficiency is 30 times more common than IgA deficiency and 1000 times more common than common variable immunodeficiency. As a component of the innate immune system, MBL is particularly important in the defense against infection in immunologically naive hosts. In a prospective, cohort study, Koch et al5 showed that children with MBL deficiency had an increased risk of acute respiratory tract infections. However, the major risk was largely confined to children 6 to 17 months of age. The risk of infection was slightly increased in children 0 to 5 months of age, and MBL deficiency was not associated with an increased risk of infection in children 18 to 23 months of age. However, other studies suggest that the risk of infection associated with MBL deficiency persists throughout childhood.3,4 MBL deficiency is also associated with serious, life-threatening infections in children. Frakking et al11 reported that MBL deficiency was associated with an increased risk of early-onset sepsis and pneumonia in neonates. Hibberd et al12 reported that MBL deficiency is associated with an increased risk of meningococcemia and meningitis in children, and it may account for one third of all cases. MBL deficiency should be suspected in children with recurrent otitis media requiring the placement of tympanos-
Mannose-Binding Lectin Deficiency in a Child with Recurrent Infections
tomy tubes or adenoidectomy; recurrent sinusitis; recurrent lower respiratory tract infection; and serious, life-threatening infections. The diagnosis of MBL deficiency is straightforward. The measurement of serum MBL concentration is available at a number of commercial reference laboratories that are used commonly by many health care facilities. Replacement therapy with purified or recombinant MBL is feasible, and it is currently being studied, but there is no information at this time concerning efficacy. Our unpublished experience suggests that prophylactic antibiotic administration may decrease the frequency and severity of infections in children with MBL deficiency. The ultimate prognosis of MBL deficiency appears to be good. An increased risk of serious infections has been reported in adults with MBL deficiency.7,13 However, in a large population-based study, Dahl et al14 found no difference in infections or mortality rates in adults with MBL deficiency compared with control subjects. In summary, MBL deficiency is common. We suggest that measuring MBL levels should be a part of the evaluation of children with increased susceptibility to infection and suspected immunodeficiency.
REFERENCES 1. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007;449:819-26. 2. Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today 1996;17:532-40. 3. Garred P, Masden HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding protein alleles in patients with suspected immunodeficiency. Lancet 1995;346:941-3. 4. Summerfield JA, Sumiya M, Levin M, Turner MW. Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ 1997;314:1229-32. 5. Koch A, Melbye M, Sorensen P, Homoe P, Madsen HO, Molbak K, et al. Acute respiratory track infections and mannose-binding lectin insufficiency during early childhood. JAMA 2001;285:1316-21. 6. Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan-binding protein with a common defect of opsonization. Lancet 1989;2:1236-9. 7. Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infection. Clin Infect Dis 2003;37:1496-505. 8. Aittoniemi J, Miettinen A, Laippala P, Isolauri E, Viikari J, Ruuska T, et al. Age-dependent variation in the serum concentration of mannan-binding protein. Acta Paediatr 1996;85:906-9. 9. Sumiya M, Super M, Tabona P, Levinsky RJ, Arai T, Turner MW, et al. Molecular basis of opsonic defect in immunodeficient children. Lancet 1991;337: 1569-70. 10. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 2000;120:225-31. 11. Frakking FNJ, Brouwer N, van Eijkelenburg NKA, Merkus MP, Kuijpers TW, Offringa M, et al. Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. Clin Exp Immunol 2007;150:255-62. 12. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999;353:1049-53. 13. Summerfield JA, Ryder S, Sumiya M, Thursz M, Gorchein A, Monteil MA, et al. Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet 1995;345:886-9. 14. Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med 2004;199:1391-9.
451