Impact of mannose-binding lectin deficiency on burden of infection in patients with hematological malignancies receiving chemotherapy

Abstract EN

The consequences of infection in patients with hematological malignancies are substantial.

The main causes of infection are both chemotherapy and disease-induced neutropenia.

Although all patients’ will eventually have neutropenic episodes, not all will suffer equally from the associated " Mannose-Binding Lectin (MBL) is a collagenous lectin.

It activates the complement system independently of antibodies and enhances phagocytosis and modification of cellular activation.

Deficiency of MBL is associated with a common defect of opsonisation, which predispose to infectious illness.

Relatively high frequency of MBL gene mutations are found within Eurasian and sub-Saharan African populations.

MBL deficiency is clinically most apparent in the context of co-existent immune defects, such as neutropenic episodes.

The aim of the study was to investigate the role of MBL in influencing the frequency and severity of infections in patients' under-going chemotherapy for hematological malignancies.

Patients and methods: we enrolled 85 patients with hematological malignancies; and a group of 40 healthy blood donors as controls.

The patient's clinical notes were assessed for frequency and duration of fever, and type of infection for 6 months from the time of diagnosis, during the whole course of chemotherapy and with relapses.

Diagnosis of organism responsible for febrile illness was performed using appropriate culture media and serologic tests; each febrile episode was reported as clinically significant or insignifiant episode.

Serum MBL concentrations were determined by a sandwich enzyme-linked immunosorbent assay (sandwich ELISA).

We used blood samples taken at the time of diagnosis, 2 days after completing a course of chemotherapy,and during febrile neutropenic episodes in daysl,7 and 14.

Results; 18(21.1%) patients had acute lymphoblastic leukemia (ALL), 6 of them relapsed; 12 (14.1%) patient had acute myeloid leukemia (AML), -٩ developed relapses, 7(8.2%) had chronic lymphocytic leukemia (CLL), 7(8.2%) had chronic myeloid leukemia (CML), 9(10.5%) had Hodgkin’s lymphoma, 10(11.7%) had non-Hodgkin lymphoma, 9(10..؟%) had sever aplastic anemia, 5(5.8%) had myelodysplastic syndrome, and 8 (9.4%) had multiple myeloma.

١٧^ identified 205 infectious episodçs, 163 W'ere clinically significant episodes, defined as bacteraemia in 49(30%) patients, pneumonia in 34(20.8%) patients, or both in 15 (9.2%) patients, cellulitis in 28(17.1%) patients, erythema gangrenosum in 8(4.9%) patients, erythema multiform in 6(3.6%) patients, necrotizing colitis in 4(2.4%) patients, meningitis in 7(4.2%) patients, encephalitis in 6(3.6%) patients, and hemorrhagic cystitis in 6(3.6%) patients.

The median concentration ofMBE of patients and healthy control subjects werel906 ng /L (range; 146-4210), and 1970 ng/1 (range: 701-31 12) respectively.

The difference was statistically insignificant (P>0.05).

According to MBL values at time of diagnosis, 46(54.2%) patients were MBL-sufficient, while 39(45.8%) cases were MBL-deficient, having MBL concentrations below 1000ng/l.

MBL-deficient patients had twice as many total days of febrile neutropenia (Median 23.1 days), as MBL-sufficient patients (Median 11.3 days, ?<0.01).

?atients with the lowest MBL concentration had longer periods of febrile neutropenia (PcO.Ol).

In the MBL deficient patients, the median number of single infectious episodes was 3.1, whereas in MBL-sufficient patients it was 1.8 (? <0;05).

The increase in total days of febrile neutropenia was Azzazi MO and Ism، 136 predominantly due to the duration of each febrile episode.

The median duration of $uch episodes in the MBL-su؛'ficient patients was 5.0 days whereas for MBL deficient patients, it was 8.5 days (?<0.01).

Results of analysis for multiple infection episodes (cumulative total) showed similar patterns (P<0.01).

Patients with MBL-deficiency had more clinically significant episodes than MBL-sufficient patients (104 and 59 episodes respectively, pcO.Ol).

.Of_12 patients admitted to the intensive-therapy unit with sever infection, 10 were MBL-deficient.

Mortality due to overwhelming infection was reported in five MBL-deficient patients, compared to none of the MBL-sufficient group (PcO.Ol).

In MBL-sufficient patients the median concentration of MBL increased to 2510 ng/1 at day 1 of febrile neutropenia, and to 5670 ng/1 at day 7, compared with the median of 3140 ng/1 seen at diagnosis, but had declined by day 14 tol740 ng/1.

By contrast, in MBL-deficient patients concentrations of the protein in serum did not alter significantiy during neutropenic episodes, being 590ng/l at day 1, 410 ng/1 at day 7 and 386 ng/1 at dayl4, compared with the median of 580 ng/1 seen at diagnosis (P>0.05).

Conclusion: ©٧٢ results suggest that MBL deficiency, in the context of disruption of innate immunity by chemotherapy, is associated with worsening 0؛' outcome in febrile neutropenic patients.

Determination of the MBL status of patients receiving chemotherapy would be beneficial to identify those at risk of infections.

Such screening could be achieved by a simple serum protein assay or by genotyping.

The identification of the most at-risk patients would permit the use of appropriate measures, could improve the out come of chemotherapy, and may reduce morbidity and/or mortality.