Elsevier

The Lancet

Volume 358, Issue 9282, 25 August 2001, Pages 614-618
The Lancet

Articles
Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study

https://doi.org/10.1016/S0140-6736(01)05776-2Get rights and content

Summary

Background

Infection is a major cause of morbidity and mortality in children with malignancy. Individuals with serum deficient in mannose-binding lectin (MBL)—an important component of the innate immune system—are more susceptible to infection than those with adequate concentrations. In this study, we investigated the capacity of this protein to influence infectious complications in children undergoing treatment for malignancy.

Methods

We enrolled 100 children receiving chemotherapy for malignancy at a children's hospital in London, UK. The frequency, duration, and causes of febrile neutropenic episodes were recorded, and MBL genotype and phenotype were determined by heteroduplex analysis and ELISAs, respectively. Serial MBL concentrations were also measured in patients during febrile episodes, and the results correlated with the MBL genotype (A/A indicating wild type, O/O indicating homozygous for MBL structuralgene mutations, and A/O indicating heterozygous for such mutations).

Findings

In the A/A patients, MBL concentrations almost doubled by day 7 of the febrile neutropenic episode before declining by day 14 (p=0·004). By contrast, in patients with MBL mutations, concentrations did not alter significantly during the neutropenic episode. In the 6 months after initial diagnosis, most patients had at least one febrile neutropenic episode, but the median duration in patients with MBL mutations was twice as long as that in children with the wildtype genotype (20·5 days vs 10·0 days; p=0·014). Individuals with the lowest serum MBL concentrations at the time of diagnosis (<1000 μg/L) had a higher median number of days of febrile neutropenia than did individuals with higher concentrations of MBL (p=0·012).

Interpretation

MBL deficiency seems to have an important influence on the duration of febrile neutropenic episodes in children with malignancy. This finding suggests that MBL infusions could represent a new therapeutic approach which would aid the management of chemotherapy-induced complications in this population of children.

Introduction

In the Western world, more than one in 600 children will develop a malignancy in the first 15 years of life.1 Although there have been major advances in therapy, most children have chemotherapy-associated complications, the commonest of which is infection.2, 3 The consequences of infection in these patients are substantial, and include infection-associated mortality (65%2 and 2%3 of treatment-related deaths in patients with acute myeloid leukaemia [AML] and acute lymphoblastic leukaemia [ALL], respectively), organ dysfunction, antibiotic-associated complications, delays in chemotherapy administration, and lengthy and frequent hospital admissions. The main cause of infection is chemotherapy and disease-induced neutropenia.2 However, although all patients will have neutropenic episodes, not all will suffer equally from the associated complications. The reasons for this finding are unclear.

Mannose-binding lectin (MBL) is a collagenous lectin (collectin) found in serum. It binds to mannose and Nacetyl glucosamine residues when presented in the orientations and densities commonly found on microorganisms.4 On binding, it activates the complement system independently of antibodies via two associated serine proteases, MBL-associated serine protease 1 and 2. The latter cleaves C4 and then C2 to form the C3 convertase, C4b2a.5, 6 Cellular receptors for MBL have been proposed, and several studies have shown direct interactions of MBL with phagocytic cells, resulting in enhanced phagocytosis and modification of cellular activation.7 Deficiency of MBL was first identified in human beings in association with a common defect of opsonisation in children.8 Subsequent studies of consecutive9 and prospective10 series of children have confirmed that MBL deficiency predisposes to infectious illness.

Human deficiency of MBL is now known to be predominantly caused by point mutations within exon 1 of the MBL gene at codons 52, 54, or 57 (termed B, C, and D variants, respectively) which result in aminoacid substitutions that compromise assembly of functional oligomers.4 Individuals heterozygous for these mutations have reduced concentrations of MBL in serum, whereas the protein is almost absent from the serum of homozygotes and compound heterozygotes.11 In addition to the exon 1 mutations, there are three major polymorphisms in the promoter region of the MBL gene, and one of these variants (X/Y) also profoundly influences expression of the protein.12, 13 The MBL promoter polymorphisms are expressed as four haplotypes called HYP, LYP, LXP and LYQ. These are in linkage disequilibrium with the exon 1 polymorphic variants, so that the D variant is linked to the HYP promoter haplotype, the B variant is linked to the LYP haplotype, and the C variant is linked to LYQ. The wildtype (A) exon 1 sequence is found in association with all four promoter haplotypes. In our study, promoter and exon 1 variants for each individual were combined to give a complete MBL haplotype—ie, HYPA, LYPA, LXPA, LYQA, HYPD, LYPB, or LYQC. More than a third of the population will have haplotypes that predispose to low MBL concentrations, and very low concentrations are expected in 12%.11

MBL deficiency is thought to be clinically most apparent in the context of co-existent immune defects,8 including primary and secondary immune deficiencies. We aimed to investigate the possible part played by MBL in influencing the frequency and severity of infections in children undergoing chemotherapy for malignancy.

Section snippets

Patients

From November, 1997, to March, 1999, we enrolled all children (⩽17 years of age) diagnosed with cancer at the Haematology and Oncology Departments of Great Ormond Street Hospital for Children, London, UK. Patients admitted for a bone-marrow transplant were excluded. Approval for the study was granted by the Great Ormond Street Hospital for Children/Institute of Child Health Research Ethics Committee, and parental consent was obtained.

Procedures

We used blood surplus to clinical requirements taken at the

Results

100 children with malignancies were enrolled. The mean age at enrolment was 5·4 years (range 4 weeks–17 years; 57 boys). There was no significant difference in age distribution between the two groups studied (ie, children of A/A genotype vs children of A/O or O/O genotype). Similarly, there was no significant difference between the genotype groups with respect to sex or diagnostic group (Kruskal-Wallis tests for all comparisons). Some eligible patients were not enrolled because of

Discussion

This study shows that innate immune mechanisms are an important determinant of the infectious burden of cancer patients undergoing chemotherapy. MBL deficiency was associated with a two-fold increase in the number of febrile days experienced by children receiving chemotherapy for malignancy. This effect was apparent in patients with MBL concentrations of less than 1000 μg/L and was not restricted to patients who were homozygous for exon 1 mutations. Thus, up to 40% of patients11 could be at

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