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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 158-162

Serum immunoglobulin subclass levels in non-hodgkin's lymphoma in Ibadan, South western Nigeria


Department of Haematology, University of Ibadan and University College Hospital, Ibadan, Oyo State, Nigeria

Date of Submission27-Oct-2020
Date of Decision16-Jan-2021
Date of Acceptance06-Mar-2021
Date of Web Publication21-Oct-2021

Correspondence Address:
Dr. Foluke Atinuke Fasola
Department of Haematology, University of Ibadan, Oyo state
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_205_20

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  Abstract 

BACKGROUND: Change in immunoglobulin (Ig) subclass levels, a manifestation of altered immune status, is thought to contribute to pathogenesis of non-Hodgkin's lymphoma (NHL). Furthermore, pretreatment Ig level in NHL patients scheduled to receive immunotherapy has prognostic significance.
AIMS AND OBJECTIVES: This study was carried out to provide information on the levels of Ig subclass in patients with NHL in our center.
METHODS: A descriptive cross-sectional study of patients diagnosed with NHL over an 8-month period was conducted. Controls were apparently healthy voluntary blood donors. Clinical information and results of hematology and clinical biochemistry investigations were retrieved from patients' case notes. The working formulation classification was used to subtype the NHL. Serum IgG, IgA, IgM, and IgE concentrations were assayed for for the levels in patients and controls.
RESULTS: A total of 68 participants (cases n = 35, controls – 33) were included in this study. The mean age of the patients was 48.67 ± 17.3 years (range: 18–85). The hematological and clinical biochemistry results were within reference values for the population except hematocrit (Hct) which was low (28% ± 7%) and high erythrocyte sedimentation rate of 72 mm/h (interquartile range [IQR] – 52.0–100.0). IgD levels were significantly lower in the cases than the controls (P = 0.029) with a Cohen's medium effect size. There was a significant drop in IgE from Stage I to III of the disease (χ2(3) = 7.93, P = 0.047). Furthermore, there were significant positive correlations between IgD, IgA, IgM, and Hct and platelets.
CONCLUSION: Immune paresis is associated with progressive disease or late clinical presentation, and this should be taken into consideration when managing these patients.

Keywords: Complete blood count, non-Hodgkin's lymphoma, serum immunoglobulin subclasses


How to cite this article:
Fasola FA, Olaniyi JA, Kotila TR, Ogundeji SP. Serum immunoglobulin subclass levels in non-hodgkin's lymphoma in Ibadan, South western Nigeria. J Appl Hematol 2021;12:158-62

How to cite this URL:
Fasola FA, Olaniyi JA, Kotila TR, Ogundeji SP. Serum immunoglobulin subclass levels in non-hodgkin's lymphoma in Ibadan, South western Nigeria. J Appl Hematol [serial online] 2021 [cited 2021 Dec 7];12:158-62. Available from: https://www.jahjournal.org/text.asp?2021/12/3/158/328721




  Introduction Top


Lymphoma consists of a group of heterogeneous disorders of the lymphoid system that has a complex immune association in terms of etiology and/or risk factors and functions. There is an increasing rise in the incidence of lymphoma in Africa. The estimated incidence of lymphoma in Africa presently stood at 3.9/100,000/year, and the total expected new cases may double over the next 2 decades, from approximately 25,000 in 2012 to more than 48,000 by 2035.[1]

An emerging risk factor for lymphoma which is still being studied is the hygiene hypothesis which proposed that delay in exposure to a certain infection is associated with increased risk of lymphoma-causing mutation in the naïve immune competent cells.[2] This is also closely corroborated by the atopic/allergy theory that shows, however with conflicting report, that self-report of allergy/atopy is associated with reduction in lymphoma incidence.[3],[4] These two theories, therefore, suggest that early and somewhat continuous stimulation of the immune system prevents the acquisition of aberrant cancer-causing mutation.

One important determinant of immune status is immunoglobulin (Ig) levels. There are conflicting reports on the levels of Ig concentrations in lymphoma patients. While some studies reported reduction, others did not find any significant reduction compared with controls.[5],[6],[7] Reduced Ig levels in lymphoma are generally believed to be a result of immune dysregulation from infiltration of the lymph node.[1] However, studies have also shown, though not entirely consistent, that IgE levels are significantly higher in controls than lymphoma patients which is in keeping with the hypothesis that allergy/atopy is associated with low risk of developing lymphoma.[8],[9] Again, the finding of reduced IgE in lymphoma patients may not be causal but a result of immune dysregulation associated with the disease.[9],[10]

The etiology of the lymphoproliferation is unknown, but immune dysregulation has been linked with development of lymphomas. Individuals with selective IgA deficiency and very high serum IgE levels associated with autosomal dominant hyper-IgE syndrome have higher risks of developing lymphoma.[11] This is despite the suggested theory that allergy/atopy protects against non-Hodgkin's lymphoma (NHL). Besides the theories associating Ig level to the biology of lymphoma, rituximab which is effective in management of B-cell NHL is associated with hypogammaglobulinemia.[12] It is advised that baseline measurement of serum Igs before initiation of rituximab treatment should be done and levels should be monitored for long-term changes.[13]

We speculated that all Ig subclass levels may not be equally affected in NHL. Information on serum Ig level in NHL patients in our setting is scarce; therefore, we aim to establish the baseline pattern of Ig levels in patients with lymphoma in an African setting by measuring IgM, IgG, IgA, IgE, and IgD in patients with NHL.


  Methods Top


Study design

This was a descriptive cross-sectional study carried out on patients diagnosed with lymphoma receiving care at the hematology clinic of the University College Hospital (UCH), Ibadan.

Study setting

The UCH is the foremost teaching hospital in Nigeria. It is a 940-bedded facility with at least 90% occupancy rate. The study was conducted over an 8-month period between January and June 2019.

Eligibility criteria

Inclusion criteria

Consecutive patients diagnosed with lymphomas over an 8-month period were enrolled into the study. Controls for Ig assay were recruited from voluntary blood donor and apparently healthy staff members.

Exclusion criteria

  • Patients who declined consents
  • All patients who had previous chemotherapy exposure.


Data and sample collection

Patients who met the inclusion criteria were recruited into the study on confirmation of a diagnosis of NHL. Diagnoses were made by lymph node biopsy and histological diagnostic report. A structured questionnaire was used to collect sociodemographic, clinical, and laboratory details of the participants. Samples for Ig quantitation, hematological, and biochemical tests were taken before commencement of chemotherapy. For serum Ig subclass assay, 5 ml of venous blood was collected into plain bottle from all patients and controls. The blood samples were allowed to clot in room temperature, and sera were separated. Serum samples from cases and controls were stored at-20°C until testing.

Ig levels were assayed for IgG, IgA, IgM, and IgE concentrations using immunoperoxidase kits by Immunology Consultants Laboratory, Inc., Portland, OR, USA. Analysis was carried out strictly according to manufacturer's instructions. Results of complete blood count which included hematocrit (Hct), white cell count, neutrophil count, lymphocyte count, monocyte-eosinophil count, monocyte count, and platelet count at the time of diagnosis were retrieved from case note. The neutrophil: lymphocyte ratio (NLR) and lymphocyte: monocyte ratio (LMR) were calculated as follows: NLR = neutrophil/lymphocyte and LMR = lymphocyte/monocyte. Also retrieved from the case notes were results of erythrocyte sedimentation rate and biochemical results which included the following: Serum creatinine, urea, uric acid, calcium, and phosphate. The working formulation classification group was used to subtype the NHL according to clinical behavior, that is, low grade, intermediate grade, and high grade. The Ann Arbor clinical staging was used to categorize clinically according to extent of the disease.

Data analysis

The data collected were analyzed using IBM SPSS Statistics for windowsVersion 25.0. Armonk, NY: IBM Corp. Sociodemographic data are summarized as means, proportions, and percentages. The levels of the Igs were not normally distributed, therefore, results were presented as median and IQR. For variables that were normally distributed, summary statistics were presented as mean and standard deviation. Categorical variables were presented as percentages.

The Mann–Whitney U-test was used to assess the difference in Ig level between patients and control samples. Kruskal–Wallis test was employed to assess the distribution of Ig levels according to lymphoma histology type. Pearson's correlation coefficient test was performed to determine the relationships between Ig levels and hematological parameters. Fisher's exact test was used to assess the association between categorical variables. Significant P value was set at P < 0.05.


  Results Top


A total of 68 participants (cases = 35, controls = 33) were included in this study that lasted for a period of 8 months. Because of small number (two cases), Hodgkin's lymphoma was not analyzed. The mean age of the patients was 48.6 7 ± 17.3 years (range: 18–85) and the mean age for the controls was 37.7 ± 13.3 years (range: 16–54). Males constituted 74% of the cases, and the male-to-female ratio was 3:1. The patients had a mean packed cell volume of 28.8% ± 7.6% (range: 16–43), and 51% had Hct of >30%. The hematological and biochemical parameters of the patients are shown in [Table 1].
Table 1: Hematological and chemistry parameters of lymphoma patients at diagnosis

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High-grade lymphoma was the most common histological presentation 44% (12), followed by indolent which was 41% (11), and the least was intermediate-grade lymphoma (15%). About 49% of the patients presented in late clinical Stage IV with indolent lymphoma accounting for half of this although the difference was not statistically significant (Fisher's exact test[9] = 12.2, P = 0.11). Eighty-two percent (27 of 33) of the patients had diagnostic bone marrow aspiration/biopsy done as part of initial workup, and of this, 74% (20) had evidence of bone marrow involvement.

Among those who had low Hct (<30%), majority (50%) belong to those who have high-grade lymphoma, followed by indolent (31%) and intermediate (13%). This difference did not reach statistical significance (Fisher's exact test[3] = 1.8, P = 0.67). Twenty-four percent of the patients had leukocytosis (white blood cell >11.0 × 109 cells/L), and of these, majority (63%) had indolent lymphoma. Leukopenia was a rare presentation (3%), but this finding was, however, not statistically significant (Fisher's exact test[6] =5.1, P = 0.723).

[Table 2] shows the pattern of Ig levels between the cases and the controls. IgD levels were significantly lower in the cases than the controls (P = 0.029). The difference in the median of IgD between patients and controls showed medium effect size. There was no significant difference in the levels of other Igs between the patients and the controls. Assessment of the level of Ig across lymphoma clinical stage showed that there was a significant drop in IgE from Stage I to IV of the disease (χ2[3] = 7.93, P = 0.047). The other Igs did not show any significant drop or increase across clinical staging. Ig levels were also found not to be related to lymphoma histology grade. There was a significant positive correlation between IgG and Hct (r = 0.418, P = 0.016), IgG and platelets (r = 0.359, P = 0.043), IgM and Hct (r = 0.344, P = 0.05), and IgA and platelets (r = 0.373, P = 0.036) [Table 3].
Table 2: Comparison of immunoglobulin level between patients and controls

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Table 3: Correlation between immunoglobulin levels and packed cell volume and platelets

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  Discussion Top


The Ig levels in the patients with lymphoma were not significantly different from the Ig levels of the controls except for IgD which was lower in patients with lymphoma than in the controls. The low level (0.25% of the total serum Ig) and short half-life of the secreted form of the D Ig (2.8 days) in normal individuals might have contributed to significant reduction. In view of the cell surface form of IgD being found along with IgM on all mature, naïve B cells,[14] the lower level in patients might also be suggestive of the degree of immaturity of the malignant lymphoid cells. The function of IgD has been obscured for a long time and has been a subject of debate. It is suggested that it enhances local and systemic surveillance against airborne pathogens and activates proinflammatory functions. These functions are complementary to the functions of other Igs. The result of this study is not in agreement with the study by Biggar et al. who reported that patients with B-cell NHL of many types had consistently lower median Ig subclass levels than controls.[10] The low Ig may be secondary to the NHL.[15],[16] The difference in the pattern of Ig levels in our patients might be because the idiotypic determinants of the lymphomas presented in our patients might be different. The facility to phenotype the lymphoma was not available in the institution where this study was carried out. Corte et al. reported low IgD in NHL patients while high and normal levels were demonstrated in Hodgkin's lymphoma patients.[17]

The IgE levels dropped as the disease advances in patients in this study. Similar observation has earlier been reported by Melbye et al.[4] The lower IgE level with advancing disease may support the atopic/allergy theory. Normal counterparts of the immune cells in lymphoma produce Ig, but in malignancy, there is suppression of Ig production. Although our finding is not consistent with report that IgE levels are higher in controls than NHL patients. The reverse is the case with HL and NHL with elevated serum IgE levels.[7] The role of IgE in lymphogenesis cannot be determined by this study but could be considered. A positive correlation of IgD with IgE observed by another author.[18] IgE levels might not be the only Ig levels that change with disease course. The significant positive correlation of IgG with packed cell volume and platelet and IgA with platelet suggests that the Ig levels are not stable throughout the disease course. The IgG and IgA are likely to decline with change in hematological parameters in advancing disease.

Low Ig increases the risk of developing infections.[16] The similar level of Ig between patients and controls might suggest that infection may not be a major issue among our patients. A study by Casulo et al. reported 85% of the patients with normal serum Ig level.[19]

It is not surprising that the Ig levels were not associated the histology type. The correlation of the behavior of lymphomas which could also influence laboratory results in patients is much more complex than that which could be derived from the use of working formulation to classify the lymphoma. The correlation of the Ig with a more advanced classification would be more informative. The limitation of this study is the sample size and the use of working formulation classification system for the lymphoma which is not robust. However, with limited clinical reports on NHL s in indigenous sub-Saharan African population, this provides basic information to improve the management of the patients which constitutes a significant percent of our patients with hematological malignancies.

Low levels of one type or more of Ig has been associated with advanced disease.[16],[20] Low Ig may be secondary to the cancer as a result from B-cell depletion due to the replacement of lymphoid tissue and failure of normal B-cells to differentiate into plasma cells that synthesize and secrete Ig. Other possible mechanisms of hypogammaglobulinemia postulated are malnutrition, intrinsic B lymphocyte defects, or defective regulatory function of T-cells or monocytes. This study could not determine whether the etiology of associated hypogammaglobulinemia is acquired or congenital. Ig replacement therapy has been shown to reduce the frequency of bacterial infections in patients with chronic lymphocytic leukemia and NHL.[15],[16] The reduction in the various Ig levels should be taken into account when administering immunotherapy to our patients with NHLs.


  Conclusion Top


Low IgD level found in this cohort of patients and declining IgE level associated with progressive disease or late clinical presentation gave insight into the etiopathogenesis of NHL in our patients with regard to their immune status. The limitation of this study was a small sample size that such that we could not analyzed data on Hodgkin's lymphoma. Moreover, a before-and-after study design of Ig assay after administration of chemotherapy may reveal more information with respect to the clinical and prognostic significance of serum Ig levels in patients with lymphoma. We recommend a prospective study and a large sample-sized study to further explore the immune status of patients with NHL to fully understand the role of Ig subclass levels in the pathogenesis and management of this disease.

Ethical consideration

This study has been conducted in accordance with the ethical principle mentioned in the Declaration of Helsinki (2013). Informed written consent was obtained from all participants in the study.

Acknowledgments

We acknowledged the laboratory personnel of the department who were involved in the bench work of the study.

Financial support and sponsorship

This was a self-funded study.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tomoka T, Montgomery ND, Powers E, Dhungel BM, Morgan EA, Mulenga M, et al. Lymphoma and pathology in sub-Saharan Africa: Current approaches and future directions. Clin Lab Med 2018;38:91-100.  Back to cited text no. 1
    
2.
Rook GA. The hygiene hypothesis and the increasing prevalence of chronic inflammatory disorders. Trans R Soc Trop Med Hyg 2007;101:1072-4.  Back to cited text no. 2
    
3.
Vajdic CM, Falster MO, de Sanjose S, Martínez-Maza O, Becker N, Bracci PM, et al. Atopic disease and risk of non-Hodgkin lymphoma: An InterLymph pooled analysis. Cancer Res 2009;69:6482-9.  Back to cited text no. 3
    
4.
Melbye M, Smedby KE, Lehtinen T, Rostgaard K, Glimelius B, Munksgaard L, et al. Atopy and risk of non-Hodgkin lymphoma. J Natl Cancer Inst 2007;99:158-66.  Back to cited text no. 4
    
5.
Kołtan A, Kołtan S, Dębski R, Grześk E, Wysocki M, Grześk G. An assessment of selected immune parameters of patients with Hodgkin's disease. Mol Clin Oncol 2015;3:237-43.  Back to cited text no. 5
    
6.
Amlot PL, Green L. Serum immunoglobulins G, A, M, D and E concentrations in lymphomas. Br J Cancer 1979;40:371-9.  Back to cited text no. 6
    
7.
Amlot PL, Green LA. Atopy and immunoglobulin E concentrations in Hodgkin's disease and other lymphomas. Br Med J 1978;1:327-9.  Back to cited text no. 7
    
8.
Ellison-Loschmann L, Benavente Y, Douwes J, Buendia E, Font R, Alvaro T, et al. Immunoglobulin E levels and risk of lymphoma in a case-control study in Spain. Cancer Epidemiol Biomarkers Prev 2007;16:1492-8.  Back to cited text no. 8
    
9.
Nieters A, Łuczyńska A, Becker S, Becker N, Vermeulen R, Overvad K, et al. Prediagnostic immunoglobulin E levels and risk of chronic lymphocytic leukemia, other lymphomas and multiple myeloma-results of the European Prospective Investigation into Cancer and Nutrition. Carcinogenesis 2014;35:2716-22.  Back to cited text no. 9
    
10.
Biggar RJ, Christiansen M, Rostgaard K, Smedby KE, Adami HO, Glimelius B, et al. Immunoglobulin subclass levels in patients with non-Hodgkin lymphoma. Int J Cancer 2009;124:2616-20.  Back to cited text no. 10
    
11.
O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013;368:161-70.  Back to cited text no. 11
    
12.
Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open 2018;1:e184169.  Back to cited text no. 12
    
13.
Makatsori M, Kiani-Alikhan S, Manson AL, Verma N, Leandro M, Gurugama NP, et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM 2014;107:821-8.  Back to cited text no. 13
    
14.
Chen K, Cerutti A. The function and regulation of immunoglobulin D. Curr Opin Immunol 2011;23:345-52.  Back to cited text no. 14
    
15.
Molica S, Musto P, Chiurazzi F, Specchia G, Brugiatelli M, Cicoira L, et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 1996;81:121-6.  Back to cited text no. 15
    
16.
Mortaz E, Tabarsi P, Mansouri D, Khosravi A, Garssen J, Velayati A, et al. Cancers related to immunodeficiencies: Update and perspectives. Front Immunol 2016;7:365.  Back to cited text no. 16
    
17.
Corte G, Ferrarini M, Tonda P, Bargellesi A. Increased serum IgD concentrations in patients with Hodgkin's disease. Clin Exp Immunol 1977;28:359-62.  Back to cited text no. 17
    
18.
Vladutiu AO. Immunoglobulin D: Properties, measurement, and clinical relevance. Clin Diagn Lab Immunol 2000;7:131-40.  Back to cited text no. 18
    
19.
Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk 2013;13:106-11.  Back to cited text no. 19
    
20.
Maulood K, Alnaqshabandi AA. Serum immunoglobulin levels in patients with lymphoproliferative diseases in Erbil, Kurdistan Region, Iraq. Zanco J Med Sci 2017;21:1930-37.  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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