0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Investigation |

Acute Respiratory Tract Infections and Mannose-Binding Lectin Insufficiency During Early Childhood FREE

Anders Koch, MD, PhD; Mads Melbye, MD, DMSc; Per Sørensen, MSc; Preben Homøe, MD, PhD; Hans Ole Madsen, PhD; Kåre Mølbak, MD, DMSc; Christoffer Holst Hansen; Lasse Høgh Andersen; Gitte Weinkauff Hahn; Peter Garred, MD, DMSc
[+] Author Affiliations

Author Affiliations: Department of Epidemiology Research, Statens Serum Institut (Drs Koch, Melbye, Sørensen, and Mølbak and Messrs Hansen and Andersen, and Ms Hahn); Departments of Otolaryngology, Head and Neck Surgery (Dr Homøe) and Clinical Immunology, Rigshospitalet, National University Hospital (Drs Madsen and Garred), Copenhagen, Denmark.


JAMA. 2001;285(10):1316-1321. doi:10.1001/jama.285.10.1316.
Text Size: A A A
Published online

Context Hospital-based studies have found that increased susceptibility to certain infections is associated with low serum levels of mannose-binding lectin (MBL) due to MBL variant alleles. However, the contribution of MBL insufficiency to incidence of common childhood infections at a population level is unknown.

Objective To investigate the effect of MBL insufficiency on risk for acute respiratory tract infection (ARI) in unselected children younger than 2 years.

Design and Setting Population-based, prospective, cohort study conducted in Sisimiut, Greenland.

Participants Two hundred fifty-two children younger than 2 years who were followed up weekly between August 1996 and August 1998 for morbidity surveillance.

Main Outcome Measure Risk of ARI, based on medical history and clinical examination, compared by MBL genotype, determined from blood samples based on presence of structural and promoter alleles.

Results A 2.08-fold (95% confidence interval [CI], 1.41-3.06) increased relative risk (RR) of ARI was found in MBL-insufficient children (n = 13) compared with MBL-sufficient children (n = 239; P<.001). The risk association was largely restricted to children aged 6 to 17 months (RR, 2.92; 95% CI, 1.78-4.79) while less effect (RR, 1.47; 95% CI, 0.45-4.82) and no effect (RR, 1.00; 95% CI, 0.42-2.37) was shown among children aged 0 to 5 months and 18 to 23 months, respectively.

Conclusion These data suggest that genetic factors such as MBL insufficiency play an important role in host defense, particularly during the vulnerable period of childhood from age 6 through 17 months, when the adaptive immune system is immature.

Acute respiratory tract infections (ARIs) are among the most prevalent infections in childhood worldwide, with the highest incidence among children younger than 2 years.1,2 Risk factors for these infections include being male, living in crowded conditions, and being exposed to child care centers and passive smoking.1,3 However, these factors explain only a fraction of the variation in incidence between children. Mannose-binding lectin (MBL) is a serum protein believed to play an important role in the innate immune response.4 A single gene, MBL2, located at chromosome 10, codes for human MBL.5,6 Mannose-binding lectin may exert its action through binding to high mannose and N-acetylglucosamine oligosaccharides present on a variety of microorganisms, thereby activating the complement system by MBL-associated serine proteases and interacting with novel receptors on phagocytes.79 As part of the innate immune system, the protein is considered particularly important in the vulnerable period of infancy before adequate specific immune protection is established by the adaptive immune system.10

Three variant alleles have been described in exon 1 of the MBL2 gene.1113 These variants are due to 3 single-base pair substitutions at codon 54 (allele B), codon 57 (allele C), and codon 52 (allele D), which independently cause low serum MBL levels.11 The normal wild type allele is commonly designated A, and the 3 mutant alleles are designated O. All variant alleles reduce the amount of functional MBL subunits in heterozygous individuals 5- to 10-fold.14 The variant alleles affecting the structural part of the MBL gene are relatively common in many ethnic groups including Eskimos (frequency of sum of all variant alleles: 0.12) and whites (frequency of sum of all variant alleles: 0.20).14 The serum MBL concentration is further dependent on a number of nucleotide substitutions in the promoter region of the MBL2 gene.15,16 In particular, a polymorphism in codon −221 (X/Y type) has a significant effect on the MBL serum concentration with the Y promoter having high and the X having low MBL-expressing activity.1416

Hospital-based studies have shown that an increased susceptibility to bacterial and viral infections has been associated with low serum levels of MBL and MBL variant alleles1721 and with a worsened prognosis in such chronic diseases as cystic fibrosis, rheumatoid arthritis, and systemic lupus erythematosus.2224 However, MBL has never been shown to play a role in the incidence of infectious diseases on a population level.

We performed a population-based cohort study of ARI in children aged 0 to 2 years living in Sisimiut, West Greenland, to investigate whether MBL insufficiency contributes to the general morbidity in children.

Study Area and Population

Sisimiut is the second largest town in Greenland, with approximately 5300 inhabitants, of which 88% have been born in Greenland and 12% have been born outside of Greenland, primarily in Denmark. One health center serves Sisimiut with up to 5 physicians and a midwife. All health services, including medication, in Greenland are free. In this town, an open cohort of children aged 0 to 2 years was formed by April 1, 1996, and monitored for ARI on a regular basis from August 12, 1996, to August 6, 1998. The cohort comprised all children living in the town as of April 1, 1996, and included all children who were either born in Sisimiut or who had moved there before June 1, 1998. All children irrespective of ethnicity (whether Eskimo, mixed race, or white) were invited to participate. Specially trained Danish medical students and local interpreters, supervised by Danish physicians, followed up this cohort.

Program and Definitions

Children were enrolled as soon as possible after identification, but not prior to 6 weeks after birth. They were excluded from the cohort when turning age 2 years. At enrollment written informed consent was obtained from each child's parent or guardian and a structured background interview was conducted. In the monitoring period, the children were visited weekly, at which time parents were asked about their child's ARI symptoms since the last visit. If symptoms were reported, a clinical examination was performed with focus on the respiratory system, including otoscopy and tympanometry using portable tympanometers (MicroTymph2; Welch Allyn, Skaneateles Falls, NY). If any of the following physical signs were recorded, the episode was characterized as a respiratory tract infection and defined by the symptoms reported (modified from parameters set by Selwyn2): purulent nasal discharge, cough, red and bulging tympanic membrane with loss of normal landmarks and abnormal tympanometric compliance, purulent ear discharge, pharyngotonsillar erythema or exudate, respiratory rate higher than 50/min plus cough or difficult breathing, rales, stridor, wheezing, cyanosis, or subcostal chest indrawing. When clear nasal secretion was the only symptom, the episode was not characterized as an ARI.2 If the children had attended the health center during an episode with respiratory symptoms, the diagnoses made by the local physicians were also used to characterize an episode. These diagnoses included rhinitis, pharyngitis, tonsillitis, acute otitis media, croup, bronchitis, bronchiolitis, and pneumonia. A child had to be free of symptoms for 7 days before a new episode was counted. A child was considered at risk on days he or she was symptom free, including the first day of a new episode, but not during the 7 days following an episode.

The study was approved by the Scientific Ethics Committee for Greenland.

MBL Genotypes

Venous blood samples were drawn at the end of the study period. Genomic DNA was isolated from blood cells drawn in EDTA containers and stored at − 80°C in Greenland, transported by − 30°C to Denmark, and stored again at − 80°C until testing. The MBL alleles were detected as previously described.14,15 Because all 3 variant alleles have a considerable effect on MBL concentrations, they were grouped as allele O, while the normal allele was designated A. Thus, the structural genotypes A/A, A/O and O/O were obtained. On the basis of these genotypes and the effect of the promoter variants in position − 221 on the MBL serum concentration, we were able to define 6 MBL genotypes.22 The A/A group had 2 normal structural alleles with high expression promoter activity (YA/YA), 1 high and 1 low-expression promoter (YA/XA), or 2 low-expression promoters (XA/XA). The A/O group had 1 variant and 1 normal structural allele with either high-expression promoter (YA/O) or low-expression promoter (XA/O) activity. Because both the O/O group and the XA/O group have a virtually undetectable amount of MBL in the blood,22 we combined genotypes and defined an MBL-sufficient group as A/A + YA (YA/YA, YA/XA, XA/XA, and YA/O), and an MBL-insufficient group as XA/O + O/O.

Statistical Methods

For risk factor analysis, ratios of incidence and 95% confidence intervals (CIs) were used as measures of relative risk (RR). The number of episodes and the number of days at risk for each child were calculated on a monthly basis. Because each child could have respiratory events in different calendar months, the model had to account for the possible correlation between episodes from the same child. Therefore, a generalized estimating equation (GEE) method with a correlation structure between measurements from the same child was used in a model assuming a Poisson distribution for the number of episodes. A banded Toeplitz correlation structure with 6 bands was applied. With this correlation structure, episodes from the same child with a maximal interval of 7 months were considered correlated, while those with larger intervals were regarded as independent. Relative risk estimates were obtained from the GEE model, and CIs were calculated using a robust covariance estimator for the estimated effects. We used the Wald test to assess the effect of any risk factor, assuming that estimates based on the GEE method were asymptotically normally distributed.25 We have previously found that age was a strong risk factor for ARI (data not shown), and to allow dependence on age, sex, ethnicity, and calendar period, we adjusted for these factors in all risk-factor analyses. The GENMOD procedure in SAS version 6.12 was used for the GEE model.26

The population-attributable risk percentage, which is an estimate of the fraction of the total number of ARIs that would not have happened if the effect of a specific risk factor had been eliminated, was estimated as described by Bruzzi et al27 on the basis of adjusted RRs and the distribution of exposure in the episodes.

Of the 338 children eligible for participation, 294 agreed and 44 refused, for a participation rate of 87%. Acute respiratory tract infection was not stated by any of the families as a reason for not participating in the study. None of the participating children were recognized as having severe chronic diseases. Of the 294 enrolled children, 288 were at risk for ARI (ie, having no symptoms for 7 days before having an episode of ARI). Of these, blood could be sampled and MBL genotypes determined for 252 children. These included 204 Greenlandic Eskimo children, 27 children of mixed race, and 8 white children according to parents' place of birth (13 children were of unknown descent). The ethnic distribution of the 252 children with known MBL genotypes did not differ from that of children with unknown MBL genotypes (Fisher exact test, P = .29). One hundred ninety-one children (75.8%) were homozygous for the normal allele A (genotype A/A), 6 children (2.4%) were homozygous for variant alleles (genotype O/O), and 55 (21.8%) were heterozygous (genotype A/O) (Table 1). Prevalence of the normal genotype A/A was higher in Eskimo children than in children of mixed descent, both of which were higher than in white children, which did not reach statistical significance (Fisher exact test, P = .32). All variant alleles were observed in Eskimo children with B as the predominant allele (frequency: 0.08), followed by D and C at lower frequencies (0.04 and 0.01, respectively). When combining the structural alleles with promoter alleles, 239 children (94.8%) were MBL-sufficient (A/A + YA), while 13 children (5.2%) were MBL-insufficient (XA + O/O). There was a significant association between ethnicity and MBL sufficiency or insufficiency (Fisher exact test, P = .03) with Eskimo children having the lowest frequency of MBL insufficiency.

Table Graphic Jump LocationTable 1. Frequencies of Mannose-Binding Lectin (MBL) Structural and Promotor Alleles in 252 Children From Sisimiut, Greenland

The risk factor analysis showed an increased risk for ARI in children who were heterozygous or homozygous for variant alleles, with those homozygous for variant alleles having the highest risk (Table 2). When combining those heterozygous or homozygous for variant alleles, the risk was still significant compared with children homozygous for normal structural alleles (A/A). An even more pronounced effect was seen among MBL-insufficient children compared with MBL-sufficient children. There was no difference in the risk for ARI among MBL-sufficient children, while both groups of MBL-insufficient children had significantly higher RRs of ARI than the former. Compared with all MBL-sufficient children, we found MBL-insufficient children to have a 2.08-fold increased risk for ARI (P<.001). Table 3 presents the full multivariate model for the analysis of MBL-sufficient children vs MBL-insufficient children.

Table Graphic Jump LocationTable 2. Association Between Mannose-Binding Lectin Genotypes and Risk of Acute Respiratory Tract Infections (ARI) in 252 Children From Sisimiut, Greenland
Table Graphic Jump LocationTable 3. Full Multivariate Model of Association Between Mannose-Binding Lectin (MBL) Promoter Alleles and Risk of Acute Respiratory Tract Infections (ARIs) in 252 Children From Sisimiut, Greenland

Table 4 presents an analysis of interaction between age and MBL genotypes. When only looking at the structural alleles, the most pronounced effects of MBL were observed for the age groups 6 through 17 months. A clear age-dependent effect of MBL was seen, however, when comparing the groups defined as being MBL-sufficient and MBL-insufficient (XA/O + O/O). Thus, the highest risk was seen for MBL-insufficient children aged 6 through 17 months (RR, 2.92; 95% CI, 1.78-4.79). Younger children also had an increased, although not statistically significant, RR of 1.47, while there was no effect of MBL insufficiency for older children (RR, 1.00).

Table Graphic Jump LocationTable 4. Interaction Between Age and Mannose-Binding Lectin (MBL) Genotypes and Risk of Acute Respiratory Tract Infections (ARIs) in 252 Children From Sisimiut, Greenland

There was a population-attributable risk for ARI of 7.2% associated with the presence of variant alleles (A/O and O/O vs A/A), and of 2.5% associated with MBL insufficiency.

To our knowledge, our study is the first prospective population-based study of the effect of MBL on the risk for common childhood infections. Overall, MBL insufficiency (genotypes XA/O + O/O) was associated with a significant 2-fold increased RR of ARI. Detailed analyses showed, however, that the effect of MBL insufficiency was restricted to the period 6 through 17 months of age. This age group had nearly a nearly 3-fold increased risk for ARI. These findings are particularly interesting because 1 of the 2 theories of the importance of MBL in the immune response envisages the protein to play a major role in the immune defense in the vulnerable period between 6 and 18 months of age when children are depleted of passively acquired maternal antibodies and the adaptive immune system is still immature.28 However, this has not previously been demonstrated. The other hypothesis proposes a role for MBL at the time of primary contact with any pathogen at any age and before an IgM antibody response can be mounted—the so-called anteantibody hypothesis.29 Although not mutually exclusive, overall, our findings lend support to the first hypothesis, but we cannot exclude that the latter hypothesis is valid in certain situations.

It has been shown that hospitalized children and immunocompromised patients with infectious diseases including ARI and meningococcal disease have a higher frequency of MBL mutations than controls hospitalized for other reasons.1719,21 In contrast to this and to our findings, studies of children with recurrent otitis media have failed to show an association with MBL mutations.30,31 There may be a number of reasons for this discrepancy. Apart from methodological differences in prospective vs retrospective studies and in the composition of study populations, a major difference is the age group involved. We found the maximal effect of MBL insufficiency in those aged 6 through 17 months, while no effect could be demonstrated among children aged 18 through 23 months. It is difficult to extrapolate from our results to children older than 2 years, but our findings suggest that the effect of MBL insufficiency as an independent risk factor for ARI in these children is limited. By contrast, in older children and in adults, the main effect of MBL insufficiency may rather be as a disease-modifying locus in an already established disease or in situations with a concurrent immunodeficiency. This is indicated by studies showing that the clinical course and severity of diseases such as cystic fibrosis, systemic lupus erythematosus, and rheumatoid arthritis may be worse in patients carrying variant MBL alleles.2224 Another difference may be that we determined MBL insufficiency on the basis of both MBL structural alleles and promoter alleles while others considered only the structural alleles. We have previously shown that the former measure may in fact reflect the serum level of MBL better than the structural alleles by themselves, because heterozygous children (A/O) may be both MBL-sufficient and insufficient, depending on the promoter alleles.22 Correspondingly, we found a significantly increased risk for ARI in children heterozygous and homozygous for variant alleles (A/O, O/O; RR, 1.46), but it was not as high as when promoter alleles were considered also.

Finally, unlike previous investigations, we addressed ARI as a whole. The spectrum of infections was wide from rhinitis to pneumonia and bronchiolitis. The effect of MBL mutations may differ when observing different clinical manifestations or etiological agents. Because our study population was of limited size and had a low frequency of MBL variant alleles compared with populations in other studies, we were not able to further explore specific clinical manifestations or the role of microbiological agents. Different ARIs are, however, often associated. Thus, rhinitis may precede other infections such as otitis media and pneumonia. A large part of ARI is viral in origin, while acute otitis media is more often a bacterial infection. Thus, even if MBL insufficiency is found associated with bacterial infections, it may primarily be associated with decreased protection against viral infections, which in turn predispose to bacterial infections. Indeed, some of the initial observations on the role of MBL in the innate immune system were made on such viruses as the influenza virus.32

The influence of MBL insufficiency on a population basis should theoretically be more pronounced in other populations with higher incidences since we found relatively few children to be MBL-insufficient. We have previously reported that frequencies of heterozygous and homozygous variant alleles are found in 38% of white and in 48% of black populations compared with 22% and 20% as found earlier among Greenlandic Eskimos.13,31 The latter figures are comparable to the frequency of 24% found in the present population, where 81% were ethnic Eskimos. Accordingly, the population-attributable risks for MBL-structural alleles and promoter alleles in our population are probably lower than in other populations.

The high frequency of MBL variant alleles in different populations indicates that MBL polymorphisms represent a balanced genetic system favoring variant alleles arising from general selection.14 We have previously suggested that this might be due to the putative disadvantage MBL confers toward intracellular bacteria and parasites, which use the complement system to gain access to the intracellular compartment.33 Whether this genetic mechanism plays a role in current populations is unknown.

In conclusion, on a population level, we found that MBL insufficiency is significantly associated with increased risk for ARI among those aged 6 through 17 months, illustrating the importance of innate immune defense factors prior to the maturation of the adaptive immune system.

Graham NM. The epidemiology of acute respiratory infections in children and adults: a global perspective.  Epidemiol Rev.1990;12:149-178.
Selwyn BJ.for the Coordinated Data Group of BOSTID Researchers.  The epidemiology of acute respiratory tract infection in young children.  Rev Infect Dis.1990;12(suppl 8):870-888.
Denny FW, Collier AM, Henderson FW. Acute respiratory infections in day care.  Rev Infect Dis.1986;8:527-532.
Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system.  Immunol Today.1996;17:532-540.
Sastry K, Herman GA, Day L.  et al.  The human mannose-binding protein gene.  J Exp Med.1989;170:1175-1189.
Taylor ME, Brickell PM, Craig RK, Summerfield JA. Structure and evolutionary origin of the gene encoding a human serum mannose-binding protein.  Biochem J.1989;262:763-771.
Matsushita M, Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.  J Exp Med.1992;176:1497-1502.
Thiel S, Vorup-Jensen T, Stover CM.  et al.  A second serine protease associated with mannan-binding lectin that activates complement.  Nature.1997;386:506-510.
Nepomuceno RR, Henschen-Edman AH, Burgess WH, Tenner AJ. cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.  Immunity.1997;6:119-129.
Turner MW. Mannose binding protein.  Biochem Soc Trans.1994;22:88-94.
Sumiya M, Super M, Tabona P.  et al.  Molecular basis of opsonic defect in immunodeficient children.  Lancet.1991;337:1569-1570.
Lipscombe RJ, Sumiya M, Hill AV.  et al.  High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene.  Hum Mol Genet.1992;1:709-715.
Madsen HO, Garred P, Kurtzhals JA.  et al.  A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.  Immunogenetics.1994;40:37-44.
Garred P, Madsen HO, Svejgaard A. Genetics of human mannan-binding protein. In: Ezekowitz RAB, Sastry K, Reid KBM, eds. Collectins and Innate Immunity. Austin, Tex: RG Landes; 1996:139-164.
Madsen HO, Garred P, Thiel S.  et al.  Interplay between promotor and structural gene variants control basal serum level of mannan-binding protein.  J Immunol.1995;155:3013-3020.
Madsen HO, Satz ML, Høgh B.  et al.  Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America.  J Immunol.1998;161:3169-3175.
Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan-binding protein with a common defect of opsonisation.  Lancet.1989;2:1236-1239.
Garred P, Madsen HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency.  Lancet.1995;346:941-943.
Summerfield JA, Ryder S, Sumiya M.  et al.  Mannose binding protein gene mutations associated with unusual and severe infections in adults.  Lancet.1995;345:886-889.
Garred P, Madsen HO, Balslev U.  et al.  Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin.  Lancet.1997;349:236-240.
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;314:1229-1232.
Garred P, Pressler T, Madsen HO.  et al.  Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis.  J Clin Invest.1999;104:431-437.
Garred P, Madsen HO, Halberg P.  et al.  Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus.  Arthritis Rheum.1999;42:2145-2152.
Garred P, Madsen HO, Marquart H.  et al.  Two edged role of mannose binding lectin in rheumatoid arthritis.  J Rheumatol.2000;27:26-34.
Diggle PJ, Liang KY, Zeger SL. Analysis of longitudinal dataOxford, England: Oxford University Press; 1994.
 The GENMOD procedure SAS/STAT Software: Changes and Enhancements Through Release 6.12. Cary, NC: SAS Institute; 1996:21-42.
Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Estimating the population attributable risk for multiple risk factors using case-control data.  Am J Epidemiol.1985;122:904-914.
Turner MW, Super M, Singh S, Levinsky RJ. Molecular basis of a common opsonic defect.  Clin Exp Allergy.1991;21(suppl 1):182-188.
Ezekowitz RAB. Ante-antibody immunity.  Curr Biol.1991;1:60-62.
Garred P, Brygge K, Sørensen CH.  et al.  Mannan-binding protein--levels in plasma and upper-airways secretions and frequency of genotypes in children with recurrence of otitis media.  Clin Exp Immunol.1993;94:99-104.
Homøe P, Madsen HO, Sandvej K, Koch A, Garred P. Lack of association between mannose-binding lectin, acute otitis media and early Epstein-Barr virus infection among children in Greenland.  Scand J Infect Dis.1999;31:363-366.
Hartshorn KL, Sastry K, White MR.  et al.  Human mannose-binding protein functions as an opsonin for influenza A viruses.  J Clin Invest.1993;91:1414-1420.
Garred P, Harboe M, Oettinger T, Koch C, Svejgaard A. Dual role of mannan-binding protein in infections.  Eur J Immunogen.1994;21:125-131.

Figures

Tables

Table Graphic Jump LocationTable 1. Frequencies of Mannose-Binding Lectin (MBL) Structural and Promotor Alleles in 252 Children From Sisimiut, Greenland
Table Graphic Jump LocationTable 2. Association Between Mannose-Binding Lectin Genotypes and Risk of Acute Respiratory Tract Infections (ARI) in 252 Children From Sisimiut, Greenland
Table Graphic Jump LocationTable 3. Full Multivariate Model of Association Between Mannose-Binding Lectin (MBL) Promoter Alleles and Risk of Acute Respiratory Tract Infections (ARIs) in 252 Children From Sisimiut, Greenland
Table Graphic Jump LocationTable 4. Interaction Between Age and Mannose-Binding Lectin (MBL) Genotypes and Risk of Acute Respiratory Tract Infections (ARIs) in 252 Children From Sisimiut, Greenland

References

Graham NM. The epidemiology of acute respiratory infections in children and adults: a global perspective.  Epidemiol Rev.1990;12:149-178.
Selwyn BJ.for the Coordinated Data Group of BOSTID Researchers.  The epidemiology of acute respiratory tract infection in young children.  Rev Infect Dis.1990;12(suppl 8):870-888.
Denny FW, Collier AM, Henderson FW. Acute respiratory infections in day care.  Rev Infect Dis.1986;8:527-532.
Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system.  Immunol Today.1996;17:532-540.
Sastry K, Herman GA, Day L.  et al.  The human mannose-binding protein gene.  J Exp Med.1989;170:1175-1189.
Taylor ME, Brickell PM, Craig RK, Summerfield JA. Structure and evolutionary origin of the gene encoding a human serum mannose-binding protein.  Biochem J.1989;262:763-771.
Matsushita M, Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.  J Exp Med.1992;176:1497-1502.
Thiel S, Vorup-Jensen T, Stover CM.  et al.  A second serine protease associated with mannan-binding lectin that activates complement.  Nature.1997;386:506-510.
Nepomuceno RR, Henschen-Edman AH, Burgess WH, Tenner AJ. cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.  Immunity.1997;6:119-129.
Turner MW. Mannose binding protein.  Biochem Soc Trans.1994;22:88-94.
Sumiya M, Super M, Tabona P.  et al.  Molecular basis of opsonic defect in immunodeficient children.  Lancet.1991;337:1569-1570.
Lipscombe RJ, Sumiya M, Hill AV.  et al.  High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene.  Hum Mol Genet.1992;1:709-715.
Madsen HO, Garred P, Kurtzhals JA.  et al.  A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.  Immunogenetics.1994;40:37-44.
Garred P, Madsen HO, Svejgaard A. Genetics of human mannan-binding protein. In: Ezekowitz RAB, Sastry K, Reid KBM, eds. Collectins and Innate Immunity. Austin, Tex: RG Landes; 1996:139-164.
Madsen HO, Garred P, Thiel S.  et al.  Interplay between promotor and structural gene variants control basal serum level of mannan-binding protein.  J Immunol.1995;155:3013-3020.
Madsen HO, Satz ML, Høgh B.  et al.  Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America.  J Immunol.1998;161:3169-3175.
Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan-binding protein with a common defect of opsonisation.  Lancet.1989;2:1236-1239.
Garred P, Madsen HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency.  Lancet.1995;346:941-943.
Summerfield JA, Ryder S, Sumiya M.  et al.  Mannose binding protein gene mutations associated with unusual and severe infections in adults.  Lancet.1995;345:886-889.
Garred P, Madsen HO, Balslev U.  et al.  Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin.  Lancet.1997;349:236-240.
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;314:1229-1232.
Garred P, Pressler T, Madsen HO.  et al.  Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis.  J Clin Invest.1999;104:431-437.
Garred P, Madsen HO, Halberg P.  et al.  Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus.  Arthritis Rheum.1999;42:2145-2152.
Garred P, Madsen HO, Marquart H.  et al.  Two edged role of mannose binding lectin in rheumatoid arthritis.  J Rheumatol.2000;27:26-34.
Diggle PJ, Liang KY, Zeger SL. Analysis of longitudinal dataOxford, England: Oxford University Press; 1994.
 The GENMOD procedure SAS/STAT Software: Changes and Enhancements Through Release 6.12. Cary, NC: SAS Institute; 1996:21-42.
Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Estimating the population attributable risk for multiple risk factors using case-control data.  Am J Epidemiol.1985;122:904-914.
Turner MW, Super M, Singh S, Levinsky RJ. Molecular basis of a common opsonic defect.  Clin Exp Allergy.1991;21(suppl 1):182-188.
Ezekowitz RAB. Ante-antibody immunity.  Curr Biol.1991;1:60-62.
Garred P, Brygge K, Sørensen CH.  et al.  Mannan-binding protein--levels in plasma and upper-airways secretions and frequency of genotypes in children with recurrence of otitis media.  Clin Exp Immunol.1993;94:99-104.
Homøe P, Madsen HO, Sandvej K, Koch A, Garred P. Lack of association between mannose-binding lectin, acute otitis media and early Epstein-Barr virus infection among children in Greenland.  Scand J Infect Dis.1999;31:363-366.
Hartshorn KL, Sastry K, White MR.  et al.  Human mannose-binding protein functions as an opsonin for influenza A viruses.  J Clin Invest.1993;91:1414-1420.
Garred P, Harboe M, Oettinger T, Koch C, Svejgaard A. Dual role of mannan-binding protein in infections.  Eur J Immunogen.1994;21:125-131.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 267

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles