|Year : 2015 | Volume
| Issue : 4 | Page : 199-205
Immuno-hematological abnormalities of human immunodeficiency virus-1 infected highly active antiretroviral naïve adults in Zaria, Northern Nigeria
Aliyu Ahmadu Babadoko, Haruna Mohammed Muktar, Aisha Indo Mamman
Department of Haematology and Blood Transfusion, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
|Date of Web Publication||21-Jan-2016|
Dr. Aliyu Ahmadu Babadoko
Department of Haematology and Blood Transfusion, Ahmadu Bello University Teaching Hospital, Zaria
Source of Support: None, Conflict of Interest: None
Background: In HIV-1-infected adults, hematological derangements include peripheral cytopenias and bone marrow abnormalities. The level of the CD4+ T lymphopenia is presently considered as one of the best markers of HIV induced immune impairment. Multiple interacting factors contribute to the hematological manifestations of HIV infection. We compare the prevalence of peripheral cytopenias and the level of immunological deterioration in treatment naïve HIV-1 infected patients.
Patients and Methods: Four hundred consecutive HIV-1 infected patients undergoing pre-treatment (Highly active antiretroviral therapy naïve) assessment were recruited at the HIV sub-specialty clinic of Ahmadu Bello University Teaching Hospital, Zaria, Nigeria between May 2003 and October 2004. A cross-sectional study of baseline hematological and immunological parameters was undertaken after confirmation of HIV-1 infection by double ELISA methods; complete blood count and CD4+ T cell count (Dynal ® ) were analyzed by manual techniques.
Results: Anemia is the most common peripheral cytopenia, 73% in male and 54% in the females. Neutropenia occurred in 10.8% of the patients while 6.25% had thrombocytopenia. Packed cell volume and Absolute lymphocyte count is associated with a reduction of CD4+ T cell counts but this is not consistent following gender and CDC clinical/immunological staging. CD4+ T cell counts decreases significant from asymptomatic stage A through symptomatic stages B to stage C p < 0.001.
Conclusion: This study demonstrates that anemia and low CD4+ T cells are the commonest hematological complication in HIV-1 infected patients and these cytopenias deteriorates with increasing advanced stages of the infection.
Keywords: Cytopenias, HIV-1 infected adults, highly active antiretroviral therapy naïve, anemia and low CD4+ T cells
|How to cite this article:|
Babadoko AA, Muktar HM, Mamman AI. Immuno-hematological abnormalities of human immunodeficiency virus-1 infected highly active antiretroviral naïve adults in Zaria, Northern Nigeria. Arch Int Surg 2015;5:199-205
|How to cite this URL:|
Babadoko AA, Muktar HM, Mamman AI. Immuno-hematological abnormalities of human immunodeficiency virus-1 infected highly active antiretroviral naïve adults in Zaria, Northern Nigeria. Arch Int Surg [serial online] 2015 [cited 2019 Aug 20];5:199-205. Available from: http://www.archintsurg.org/text.asp?2015/5/4/199/174658
| Introduction|| |
Peripheral blood cytopenias and immune paresis are common in human immunodeficiency virus (HIV) infection and increase in frequency with advancing disease. The mechanisms of these changes are multiple; quantitative and qualitative marrow defects and immune cytopenias are a direct result of HIV infection while the varied assault of opportunistic infections, lymphoma, and a myriad of drugs against infection, malignancy, or HIV itself play an important role.  Anemia is the most common hematological abnormality in HIV infection, with an estimated prevalence of 63-95%. ,,,
Anemia of chronic disorder, which is due to abnormal cytokine expression and alteration of bone marrow microenvironment is the commonest cause. , Neutropenia increases in incidence as the disease progresses although it may be present in asymptomatic individuals. , Impaired hemopoiesis is the major factor although immune neutrophil destruction may contribute as antineutrophil antibodies that have been detected in some HIV antibody positive patients.  Thrombocytopenia is common in all stages of HIV disease and may be the presenting feature.  An immune basis has been strongly suggested in many patients by the presence of increased number of megakaryocytes in the bone marrow, platelet-associated immunoglobin G (IgG) and complement, and by the response to conventional treatment for immune thrombocytopenic purpura (ITP).  Thrombocytopenia may also result from marrow impairment, toxic drug effects, or the effects of splenomegaly. 
The level of the immune status is measured by the CD4+ T lymphocyte count (CCC) as it correlates with the development of opportunistic infections.  HIV has selective tropism for CD4+ T cells and other CD4+ cells, particularly monocytes, macrophages, Langerhans, and dendritic cells. , Infection of these cells by HIV result in direct lysis of the peripheral CD4+ T cells.  Approximately 100 billion new viral particles are produced every day, and 1-2 billion CD4+ T cells die every day. 
This study was conducted to determine and compare the magnitude and severity of hematological and immunological derangements and their relationship in HIV-1 positive individuals who have not being exposed to any form of conventional antiretroviral agents. This will provide a basis for the strengthening of supportive care prior to the commencement of highly active antiretroviral therapy (HAART).
| Patients and Methods|| |
This was a cross-sectional study of 400 adult HAART naïve HIV-1 infected patients at the Ahmadu Bello University Teaching Hospital (ABUTH) Haematology HIV subspecialty clinic between May 2003 and October 2004. The hospital has an antiretroviral therapy (ART) center that provides voluntary counseling and testing, care and treatment for HIV-infected pregnant women, children, and adults. There were 20 HIV negative healthy adult controls. Pregnant women pediatric patients (children <18 years), patients on HAART, and patients with opportunistic infections and malignancies (such as tuberculosis, leukemias/lymphomas, Kaposi's sarcoma, and nephropathies) were excluded from the study. Ethical clearance was obtained from the Hospital Health Research Committee and all participants signed an informed written consent. To ensure confidentiality of data, the study participants were identified using codes.
All study subjects had a detailed history and physical examination conducted and thereafter they were sent to the laboratory where 10 mL of their venous blood sample was collected into an anticoagulant bottle. This was used for the determination of some laboratory parameters; HIV-1 was confirmed by double enzyme-linked immunosorbent assay (ELISA) tests (STATPAK and GENIE II), packed cell volume (PCV), total white blood cell (WBC) count, platelet count (PLT), and blood film preparation/differential counts were determined by standard manual methods.  Automated machines were not available as at the time of the study. Absolute neutrophil count (ANC) was calculated as a percentage of the WBC count. Anemia was defined according to the World Health Organization (WHO) criteria, as PCV of <40% in males and <35% in females.  CD4+T cell count was determined by using monoclonal antibody labeled microspheres (Dynal manual method) developed in Oslo, Norway.
Patients are stratified according to gender and by Centers for Disease Control and Prevention (CDC) staging of the disease. The results are presented as median and standard error (SE) in text and tables. One Sample Kolmogorov-Smirnov test was used to determine the normality of the variables. Thereafter a nonparametric test was used to determine the differences between the hematological parameter and CD4+ T cell count of the HIV-positive patients and the control group (HIV-negative) and between the genders in the HIV-positive group using Mann-Whitney test. The variables were also compared between the various disease stages of HIV severity using Kruskal-Wallis H test. Linear regression was used to test for the degree of association between CD4+ T cell count and test parameters and regression line graph are presented as figures (PCV, total WBC cell count, absolute neutrophil count, absolute lymphocyte count, and platelet count) Data were analyzed using Statistical Package for Social Sciences (SPSS) version 20 computer software (IBM Corp. Released 2011, Armonk, NY). A P value of 0.05 or less was considered to be statistically significant.
| Results|| |
Demographic and social characteristics of the participants
There were 400 HIV-1 positive participants with age ranging from 15 years to 64 years, and majority of the participants were in the age group of 25-44 years (76%) [Table 1]. The median age of the participants was 34.2 years with a SE of 0.33; the participants comprised 187 (46.8%) males and 213 (53.3%) females. The median age of the males was 35.0 with a SE of 0.66 while the females had a median age of 31.0 with a SE of 0.55. Although the males were older than the females, there was no significant difference in their ages (P = 0.133). Two hundred and sixty four (66%) patients were married while 92 (23%) were single and the remaining 44 (11%) patients were either divorced or widowed. Three hundred and ninety seven (99.25%) patients claimed to have acquired the infection through heterosexual contact and only three (0.75%) through transfusion of infected blood but this could not be substantiated. CDC clinical/immunological stage distribution showed that 108 (27%) patients were in stage A, 153 (38.5%) in stage B while stage C had 139 (34.8%) patients [Table 2].
Hematological and immunological parameters
PCV of the participants ranged from 12.0 to 50.0% with a median of 34.0%. Out of the 187 males 137 (73.26%) had anemia while out of the 213 females only 116 (54.46%) had anemia [Table 3]. Platelet count ranged from 55.0 to 490.0 × 10 9 /L with a median of 188.0 × 10 9 /L [Table 4]. Twenty-four (6.0%) study participants had platelet count of less than 100.0 × 10 9 /L - "thrombocytopenia." Total WBC ranged from 1.1 to 20.1 × 10 9 /L with a median of 5.15 × 10 9 /L. Twenty-six (6.5%) patients had total WBC of less than 3.0 × 10 9 /L ("leukopenia"). Absolute lymphocyte count ranged from 0.096 to 4.96 × 10 9 /L with a median of 1.92 × 10 9 /L [Table 4]. PCV and the CD4+ T cell count were significantly lower from that of the control (P < 0.001) [Table 4]. Immunohematological variables were compared following stratification by gender and clinical/immunological staging [Table 5] and [Table 6]. The PCV of the males were significantly higher than that of the females (P = 0.022) [Table 5]. The PCV, total WBC count, platelet count and CD4+ T cell count decreased significantly from stage A through B to C (P =<0.001, 0.047, 0.035, and <0.001, respectively) [Table 6].
|Table 3: Distribution of cytopenias in all the participants and by gender |
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|Table 6: Immunohematological profile of the participants by CDC clinical/immunological stage |
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CD4+ T cell count
The CD4+ T cell count of the participants ranged from 20 cells/μl to 1,440 cells/μl with a median of 220.0 cells/μl [Table 4]. Only 58 participants (14.5%) had CD4+ cells of greater than 500 cells/μl, while a majority of the participants, i.e., 184 (46%) had CD4+ cell count between 200 cells/μl and 499 cells/μl and 158 (39.5%) participants had CD4+ cell count of less than 200 cells/μl [Table 2]. The CD4+ cell counts decreased significantly from stage A through B to C (P < 0.001) [Table 5]
Hematological and immunological abnormalities
This is shown in [Table 3], [Table 5] and [Table 6] in all the participants. It is stratified according to gender and clinical/immunological staging. Linear regression was carried out to determine the association of all the variables with CD4+ T lymphocyte counts. Only the PCV and absolute lymphocyte count showed a significant association with the CD4+ T lymphocyte count - R 0.141 R 2 0.020, P = 0.005 and R 0.117, R 2 0.014, P = 0.020, respectively. The regression line graph is shown in [Figure 1] and [Figure 2]. While the PCV remained significantly associated to the CD4+ T cell count in the females - R 0.192, R 2 0.037, P = 0.005 (regression line graph is shown in [Figure 3]), it was not significant in the males - P = 0.298. Conversely, while the absolute lymphocyte count remained significantly associated with the CD4+ T cell count in the males - R 0.215, R 2 0.046, P = 0.003 (regression line graph is shown in [Figure 4]), it was not significant in the females - P = 0.624.
|Figure 1: Regression linear graph of PCV and CCC (CD4+ T cell count) among the participants|
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|Figure 2: Regression linear graph of absolute lymphocyte count and CCC among the participants|
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|Figure 3: Regression linear graph of PCV and CCC (CD4+ T cell count) among the female participants|
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|Figure 4: Regression linear graph of PCV and CCC (CD4+ T cell count) among the male participants|
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| Discussion|| |
In this study, we found that before the initiation of HAART, anemia was the commonest hematological derangement. A high prevalence obtained in both the men and women at initial presentation [Table 3] was consistent with the findings by Erhabor et al.  in Portharcourt, Rivers State, Nigeria who reported a prevalence of 80% and Kagu, et al.  in Maiduguri, Borno State, Nigeria who reported a prevalence of 90.4%. This was also comparable to other published studies in South Africa,  USA, and Europe. ,,, However, a lower value of 37.5% was reported in the University Hospital Sau Paulo;  similarly, low values were reported in the studies by Sullivan et al. in the multistate adult and adolescent spectrum of HIV disease surveillance project.  They reported a prevalence of 10-20% at the initial presentation; an incidence of 37% among patients with clinical AIDS, 12% in patients with immunologic acquired immune deficiency syndrome (AIDS) as defined by CD4+ T lymphocytes count <200 cells/μl, and 3% among patients with neither clinical nor immunologic AIDS. Thus, the prevalence of anemia may be associated with a significant reduction in CD4+ lymphocyte count (<500 cell/μl), as was the case in our study with a fewer number of patients in the asymptomatic stage A (27.1%) where the immunological status is still preserved compared to the increased number of patients in the symptomatic stages B (38.3%) and C (34.8%) characterized by a profound immunological deterioration [Table 2]. This finding was buttressed by the significant association of PCV with CD4+ T cell count (R 0.141, R 2 0.020 P = 0.005) [See [Figure 1]]. Jose et al. also reported a moderately strong, positive correlation between PCV and CD4+ T cell count (r = 0.595, P < 0.001). 
A majority of the participants (85.5%) have CD4+ T lymphocytes count of less than 499 cells/μl [Table 2]. This was also in agreement with earlier reports by Akanmu, et al.  where cytopenias were reported to have a direct relationship with the level of immune deterioration. Although our study showed a significant correlation of PCV and CD4+ T lymphocyte count, this was in contrast to the reports by Audu et al.  in the study "Impact of Tuberculosis co-infection on the level of PCV in HIV infected patients" in which there was no correlation between PCV and CD4 count in the two groups of patients, one with only HIV infection and the other coinfected with tuberculosis. Anaemia may result from several causes ,, a reduced production of IL-3, a growth factor for erythropoiesis due to the direct affectation of HIV virus on the T lymphocytes responsible for the production of the cytokine has been reported. ,,
The range of the CD4+ T lymphocytes count of the control participants (520-1,600 cells/μl [Table 4]) was similar to the reported normal range of 500-1,500 cells/μl in the general Nigerian population.  Similarly, the mean CD4+ T lymphocyte count of the control (898 cells/μl [Table 4] was higher than that obtained from studies by Njoku et al. in Jos, Plateau State, Nigeria where the mean value was found to be 871 ± 12 cells/μl  and also in studies by Akanmu et al. in Lagos, Lagos State, Nigeria where a value of 747 ± 209 was obtained.  However, our finding compared favorably well with the results obtained in other West African communities (826 cells/μl) and was also in close agreement with the Caucasian results from USA (870-898 cells/μl). ,,,, It is also higher than the value obtained in a similar study in Europe-France (694 cells/μl).  The differences observed in our study compared to others might have been due to the smaller sample size of the control participants as well as the differences in methods of CD4+ T cell enumeration. The CD4 count of the study participants declined significantly - P < 0.001 from 506 cells/μl in stage A to 256 cells/μl in stage B to 134 cells/μl in stage C [Table 6]. This was in agreement with the fact that most symptoms begin to appear when the CD4 count is between 200 cells/μl and 250 cells/μl and the decline represents an increasing clinical severity of the infection. This finding has been reported in several other studies. ,,, This was also supported by a significant positive association between the absolute lymphocyte count and CD4+ lymphocyte count - R 0.117, R 2 0.014, P = 0.020 [Figure 2]. This may explain why some studies have proposed the use of absolute lymphocyte count as a surrogate for CD4+ T cell count in resource-limited setting.
Neutropenia was common with a prevalence of 17.5%, which was higher than reports in text of 10% reported in patients in early, asymptomatic HIV infection.  Our report is similar to the findings by Keizer et al. in United states, where 17% of the symptomatic patients infected with HIV had neutropenia.  Similarly in Nigeria, Adetifa et al. reported a prevalence of 16% in 2004 and 17.5% in 2006 in pediatric HIV infection.  As with other peripheral cytopenias in the setting of HIV infection, multiple etiologies may be present, either singly or in combination  Soluble inhibitory substances produced by HIV-infected cells have been noted to suppress neutrophil production as well as decrease serum levels of granulocyte colony-stimulating factor (G-CSF), which have been described in these patients with afebrile neutropenia (<1,000 neutrophils/μl).  Out of the total number of 43 participants with neutropenia, 25.6% (11 participants) with asymptomatic neutropenia were in Stage A where there is preservation of immune function while the majority, i.e., 20.9% (9 participants) were in the symptomatic stage B and 53.5% (23 participants) were in stage C [Table 3] associated with significant immunodeficiency. Thus, an increasing neutropenia is associated with deterioration of immunological status. However, neutropenia cannot be used as an alternative to CD4 T cell count as is reported in other studies. 
The prevalence of thrombocytopenia was 6.5% [Table 3] in our study, which was low compared to 40% obtained by Sullivan et al.  In Nigeria, Adetifa et al. reported a lower prevalence of 2.5% in 2006 in a study of 68 children with confirmed HIV infection in the Department of Paediatrics, Lagos University Teaching Hospital.  However, an incidence of 0% was reported by Karpatkin et al. in 1987 in a study of an asymptomatic group of 26 seropositive homosexual men.  Our finding is, therefore, contrary to the reports of thrombocytopenia being common in HIV infection and serving as the first clinical presentation in these patients. The majority of the participants with thrombocytopenia were in the symptomatic stages B (20%) and C (72%) while only 8% were in the symptomatic immunocompetent stage A. This was comparable to several other reports ,, and thus, may not be unconnected to the severity of infection as was demonstrated by the significant correlation of platelet count with CD4+ lymphocyte count r 0.086 and p 0.043 [Figure 3]. Direct infection and suppression of the megarkaryocyte may account for this. ,
The differences observed in this study as compared to others may be largely due to the methods of cells enumeration. Most studies use automated techniques for peripheral blood cell counts and flow cytometry as the standard technique used in determining CD4+ T lymphocyte subset. The inherent errors associated with the manual method is that a large coefficient of variation for leukocytes count for the manual method is 16% and for automated analytical method is 1.5%. The presence of coinfections (tuberculosis, malaria, enteric fevers, hepatitis B and C, HTLV-1, syphilis ,and a host of helminthes infestations) will also influence the CD4+ lymphocytes and other blood cells count.
| Conclusion|| |
Peripheral blood cytopenias are seen in HIV-infected patients and anemia is the most common mode of presentation while thrombocytopenia is rare. A large collaborative observational cohort study design and a prospective follow-up design are necessary to address questions regarding the causal relationship of cytopenias with immunological status. Further studies are also necessary to identify the etiological factor/s of these cytopenias, their effect on survival, and whether HAART may have a positive impact on reducing their prevalence in HIV/AIDS patients.
The authors thank Dr. Aminu S.M of the Department of Haematology and Blood Transfusion, ABUTH, Zaria, Kaduna State, Nigeria for the helpful discussion on the manuscript, all the resident doctors of the Haematology Department, ABUTH for patient selection, history, and examination, Matron Ogbogu N.O and Biodun O (late) for counseling and obtaining the patients' consent, Mr. John Ashie for blood sample collection, and Mrs. Ajiboye M for the evaluation of laboratory parameters.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]