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Year : 2011  |  Volume : 54  |  Issue : 3  |  Page : 542-546
Study of bone marrow changes in antiretroviral naive human immunodeficiency virus-infected anemic patients

1 Department of General Medicine, Medical College and Hospital, Kolkata, India
2 Department of Heamatology, NRS Medical College and Hospital, Kolkata, India
3 Department of Gynaecology & Obstetrics, North Bengal Medical College and Hospital, Sushrutanagar, Darjeeling, West Bengal, India

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Date of Web Publication20-Sep-2011


Background: Bone marrow changes are common throughout the course of HIV infection. There is scanty data addressing this issue in Indian subcontinent. The present study was aimed at characterizing the bone marrow changes in the antiretroviral naive HIV-infected Indian patients with anemia. Materials and Methods: This was a nonrandomized cross-sectional observational study undertaken over a period of 2 years. Forty-six randomly selected patients with documented anemia served as the study population. None of them was on any antiretroviral therapy or suffering from any known causes of anemia. All the patients underwent thorough evaluation, including bone marrow examination. Results: Majority of the patients had normocytic-normochromic anemia (63%), in tune with the available data. In most of the cases bone marrow was hypercellular (63.04%), although in a significant proportion it was found to be hypocellular (19.57%). Erythropoiesis was suppressed in 36.96% of patients. Dysplastic changes involving isolated cell lines ranged from 13.04% to 45.65%, dysmegakaryopoiesis being the most common, followed by dyserythropoiesis. Marrow plasmacytosis was detected in 23.91% of patients. No statistically significant correlation was detected in between immunological status (CD4 count) and marrow cellularity, myelodysplastic changes or marrow plasmacytosis. In a fair number of cases bone marrow examination aided in the diagnosis of opportunistic infections. Conclusions: Bone marrow changes are common in Indian HIV-infected anemic population, particularly in the advanced stages of the disease. HIV infection should be considered in the differential diagnosis of patients with secondary myelodysplasia or unexplained bone marrow changes.

Keywords: Anemia, bone marrow, CD4 count, HIV, myelodysplasia

How to cite this article:
Pande A, Bhattacharyya M, Pain S, Samanta A. Study of bone marrow changes in antiretroviral naive human immunodeficiency virus-infected anemic patients. Indian J Pathol Microbiol 2011;54:542-6

How to cite this URL:
Pande A, Bhattacharyya M, Pain S, Samanta A. Study of bone marrow changes in antiretroviral naive human immunodeficiency virus-infected anemic patients. Indian J Pathol Microbiol [serial online] 2011 [cited 2020 Nov 30];54:542-6. Available from: https://www.ijpmonline.org/text.asp?2011/54/3/542/85089

   Introduction Top

India has an estimated 2.5 million HIV infections and worldwide approximately 2.7 million people are getting newly infected with this virus every year. [1] Infection with HIV has been associated with a broad range of clinical outcomes involving the hematopoietic system. Disorders including lymphadenopathy, anemia, leukopenia and/or thrombocytopenia are common throughout the course of HIV infection. They may be the direct result of HIV, manifestation of secondary infections and neoplasm, or side effects of therapy. Anemia has been found to be the most common hematological manifestation in HIV/AIDS patients in many studies. [2] While generally mild, anemia can be quite severe and may require chronic blood transfusion. Bone marrow examination in HIV-infected patients is usually performed to evaluate peripheral cytopenias, to diagnose systemic infections or malignancies. However, in this population, abnormalities are frequently seen in all marrow cellular elements, as well as in the marrow matrix itself, even without the above-mentioned situations. [3],[4] Dysplastic changes, such as dysgranulopoiesis, Pelger-Huet anomaly in mature granulocytes, vacuolation of erythroid and myeloid cells, unilobular micromegakaryocytes, and megaloblastic erythroid precursors are all documented. [5] Apart from this, opportunistic infection and other hematological findings are also common. Pathophysiologies of these changes are often unclear.

Data related to hematological and bone marrow changes in HIV are scanty in this part of the world. There is hardly any study that described the bone marrow changes in the cohort of anemic HIV patients. The present study was aimed to characterize the bone marrow changes in the antiretroviral naive HIV-infected patients from eastern India with documented anemia.

   Materials and Methods Top

The study was conducted in the HIV clinic and the department of medicine in a tertiary care institution of India, in collaboration with the department of hematology. This was a nonrandomized cross-sectional observational study undertaken over a period of 2 years starting from February 2008 through January 2010. Study population constituted 46 randomly selected HIV patients with hemoglobin level less than 12 g/dL in women and 13 g/dL in men. [6],[7] None of them were on any antiretroviral therapy. Patients on medication for anemia, pregnant patients, known malignancies, or hematological disorders, such as thalassemias, hemophilia, and others, patients suffering from medical conditions known to cause anemia, such as chronic renal failure, hypothyroidism, and others, were also excluded from the study. Informed consent was taken from all the patients. The study got clearance from the institutional ethical committee.

All the patients underwent evaluation initially by detailed history taking, including duration for HIV seropositivity, drug history and history suggestive of opportunistic infections, thorough clinical examination with special reference to hematopoietic system, and signs of opportunistic infections. Laboratory investigation included a complete hemogram, CD4 count, bone marrow aspiration for morphology, and iron store. Also done in selected patients were bone marrow trephine biopsy and cytogenetic study, bone marrow aspiration material Ziehl-Neelsen stain for acid fast bacilli, fungal stain, fungal culture, and bactec culture (Bactec 460 TB System, Becton Dickinson, USA). HIV was diagnosed by Rapid ELISA test kit (HIV Comb, Tri-dot-J Mitra and Co. PVT. LTD., India); CD4 counts were documented by a FACS Counter (Becton-Dickinson, USA) by fluorochrome-conjugated antibody to CD4. Complete blood counts were performed on a fully automated five-part differential cell counter (SYSMEX SS 300, Kobe, Japan) from EDTA blood. Bone marrow aspirates were taken from posterior iliac crest with Salah's bone marrow aspiration needle and bone marrow biopsy when required was done with Jamshidi bone marrow biopsy needle. Marrow aspirate staining was done by Leishman stain. Bone marrow iron staining was done by Perl's stain. Bone marrow trephine biopsy was stained by hematoxylin and eosin (H-E) stain.

Results were tabulated in Microsoft office excel worksheet and expressed as mean (± standard deviation) for continuously distributed variable, and in absolute numbers and percentages for discrete variables. Appropriate standard statistical methods were utilized. Chi-square test and P value were analyzed by using MedCalc software (version, Mariakerte, Belgium); P value of less than 0.05 was considered statistically significant.

   Results Top

Complete evaluations were done in 46 patients; majority of them had advanced HIV disease. There were 32 male and 14 female patients. All of them were adult with the mean age of 39.54 years (standard deviation ± 11.13), ranging from 19 to 63 years. The study population (n = 46) had a mean CD4 count of 133.74 cells/μL (range 12-346 cells/μL) and the mean hemoglobin was 7.15 g/dL. Majority of patients had normocytic-normochromic anemia (63%), in tune with the data available in India and outside.[8],[9] [Table 1] shows the distribution of other important parameters among the study subjects.
Table 1: Distribution of parameters among study population (n = 46)

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The bone marrow findings are summarized in [Table 2]. We found hypercellular marrow in most of the cases (63.04%). Hypocellular marrow was found in 19.57% cases. Erythropoiesis was suppressed in 36.96%. Megaloblastic erythropoiesis was noted in 23.91%. Suppressed granulopoiesis and megakaryopoiesis were seen in 15.22% and 19.57%, respectively. Most important bone marrow finding of our study population was a very high prevalence of dysplastic changes [Figure 1] and [Figure 2]. Although trilineage dysplasia was seen in 6.52%, dysplastic changes involving isolated cell lines were ranging from 13.04% to 45.65%, most prevalent being dysmegakaryopoiesis followed by dyserythropoiesis [Table 3]. In the megakaryocytic series predominant dysplastic changes were micromegakaryocyte and multilobated megakaryocytes. The most common abnormalities in the erythroid precursors were megaloblastic changes followed by abnormal nuclear chromatin pattern, micronormoblasts, and vacoulation in the cytoplasm. Binucleated erythroid precursors and internuclear bridges were noted only in few cases. Myeloid dysplasias were noted less frequently, giant metamyelocyte was the most common abnormality. Hypo- and hypergranular myeloid precursors were also present in some cases. Increased number of plasma cells was found in a significant proportion of cases (23.91%). Erythrophagocytosis was seen in 6.52% cases. Bone marrow granuloma was detected in 2 patients. Ziehl-Neelsen staining revealed acid fast bacilli in 2 patients. Histoplasma was evidenced as budding yeast cells within macrophages in bone marrow aspirate of 1 patient and clusters of budding yeast cells in bone marrow trephine biopsy of another patient [Figure 3].
Table 2: Bone marrow fi ndings (n = 46)

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Table 3: Dysplastic changes involving bone marrow (n = 46)

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Figure 1: Dysmegakaryopoiesis. Bone marrow aspiration slides were stained using Leishman's reagent (x1000). This slide shows significant dysmegakaryopoietic changes in the form of multiple separate megakaryocyte nuclei, individual nuclei with bizarre opened up nuclear chromatin and cytoplasmic immaturity

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Figure 2: Dyserythropoiesis and dysmyelopoiesis. This Leishmanstained bone marrow aspiration slide (x1000) reveals marked dyserythropoietic changes, -that is, erythroblasts with nuclear multilobation, megaloblastoid erythroid maturation. Also present slide shows signifi cant dysmyelopoiesis in the form of pseudo-Pelger-Huet nuclei, myeloid nuclear hypolobation, and hypogranular cytoplasm

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Figure 3: Histoplasma in marrow trephine biopsy. Bone marrow trephine biopsy specimen showing Histoplasma capsulatum (H and E, x400)

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In the present study, statistically significant correlation was absent in between immunological status (CD4 count) and bone marrow cellularity, dysplastic changes, marrow plasmacytosis, or any other marrow changes as depicted in [Table 4].
Table 4: Correlation of bone marrow changes with immunological status (CD4 count)

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   Discussion Top

According to some literature, bone marrow abnormalities are seen in 90% of HIV-infected patients during the course of disease in the form of increased cellularity, dysplasia, or granulomatous involvement. [10] The exact mechanism of HIV-induced bone marrow changes are not known, however, these are possibly due to either direct effect of HIV, nutritional deficiencies, opportunistic infections, or bone marrow suppression by antiretroviral therapy, and other drugs used in the treatment of HIV infection. [11] Bone marrow picture in our study were characterized by hypercellular marrow in majority of the patients, as encountered in other studies. [10] Bone marrow hypocellularity was detected in 19.57% patients, which is somehow higher than available international data (approximate 5% in this group). [12] The difference is difficult to explain but it is likely to be due to different cohort of patients included in various studies. Majority of patients under the study had advanced HIV disease where bone marrow is likely to be normocellular or hypocellular rather than hypercellular, which is predominantly encountered in early stages of the disease. [13] In a study from India, Tripathi et al. [14] found bone marrow to be normocellular in 75.68%, hypocellular in 6.75% and hypercellular in 17.57% patients. Suppressed erythropoiesis was found in a significant proportion of patients in our study. Suppression or hyperplasias of granulocytic and megakaryocytic series were also documented. But these changes did not correlate well with the immunological status of the patients.

The incidence of myelodysplasia was lower in our study compared with 50%-90% reported in literature. [10] The difference in incidence of dysplasia in different populations of patients is largely unexplained. Myelodysplasia in majority of patients is directly proportionate to the HIV RNA load. [15] Higher incidence of dysplasia in advanced disease is postulated to be due to increased HIV RNA load, cytokine-mediated effect of disease, drug-related changes, and effect of infections. In our study, we selected drug naive patients, so the effect of antiretroviral drugs were absent, which can partly explain the lower detection of dysplastic changes. Tripathi et al. [14] described myelodysplastic changes to be 32.43% in a more heterogeneous patient population, where inclusion criteria included anemia, leukopenia, thrombocytopenia, or pyrexia of unknown origin. The most common cause of myelodysplasia in non-HIV population is possibly an inherent defect of hematopoietic cells. However, some patients are diagnosed with secondary myelodysplastic syndrome and important causes include drugs, alcohol, infections, such as tuberculosis and malaria. Reports are lacking on the incidence of HIV disease in patients of myelodysplastic syndrome. Nevertheless, HIV infection should be included in differential diagnosis of patients with secondary myelodysplasia. The myelodysplasia in early stages may not be reflected in peripheral blood picture, and thus may remain underdiagnosed. This also suggests that prevalence of myelodysplasia in HIV may be much higher than what is reported. No study is available, which has reported the incidence of myelodysplasia based on bone marrow examination in all HIV/AIDS patients irrespective of their hematological presentation.

In the present study, the most common dysplastic change was dysmegakaryopoiesis followed by dyserythropoiesis, in contrast to majority of publications where either dyserythropoiesis or dysmyelopoiesis is more common. [14],[15],[16],[17] The patients with features of myelodysplasia in bone marrow had predominantly normocytic blood picture (79%) with an average mean corpuscular volume of 91.5 fL. In peripheral blood smear, pancytopenia or bicytopenia were documented in a significant proportion of cases (36% each). Majority of them had a history of long-standing anemia often requiring blood transfusion. As per the information available, this HIV-related myelodysplastic syndrome (MDS) differs from primary MDS because the former variety often responds to HAART therapy and the chances of transforming into acute leukemia is also negligible. [18],[19],[20],[21] Bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute an entity for which the name HIV-myelopathy has been proposed in the literature. [22]

In our study, infiltrations of marrow by tumor or parasite were conspicuous by their absence except in 1 patient who was detected to have Hodgkin's disease as already mentioned. Two more patients were detected with bone marrow granuloma, among them one was later diagnosed to be due to disseminated tuberculosis. Hemophagocytosis was detected in the marrow of 3 patients. It is commonly found, to varying degrees, in the bone marrow of HIV-infected individuals without an underlying diagnosis of hemophagocytic lymphohistiocytosis (HLH), which raises the possibility of a subclinical form of HLH. [23] Among the above 3 patients, only 1 fulfilled all the criteria of HLH. Marrow iron status was adequate in most of the patients, so iron deficiency was excluded as a major contributor of anemia. Increased number of plasma cells was found in a significant proportion of cases (23.91%), in majority of them neither M components were detected in serum protein electrophoresis nor there any other features of multiple myeloma found. Various studies have reported that plasma cells in bone marrow are increased in all patients with HIV infection. [24] One study documented plasmacytosis ranging from 57.89% to 65.45% according to stage of the disease. [14] Marrow plasmacytosis was not only confined to those with advanced disease in whom opportunistic infections could be implied with but was also seen in patients at an early stage where concurrent infections were absent. So it is postulated that increased plasma cells could be a polyclonal B cell response to HIV infection and can occur at any stage of HIV disease. Although our patient population had plasmacytosis, the level was much lower compared with national and international literature. In spite of anemia being the sole criteria for case selection in our study, many of the patients were later detected with other opportunistic infections. So the reason behind lower plasmacytosis was largely unexplained.

   Conclusions Top

Bone marrow changes are common in Indian HIV-infected anemic population, particularly in the advanced stages of the disease. In majority the marrow were hypercellular, although in a significant proportion it was found to be hypocellular. Marrow plasmacytosis was detected in 23.91% of patients. In a fair number of cases bone marrow examination aided in the diagnosis of opportunistic infections. Dysplastic changes involving isolated cell lines ranged from 13.04% to 45.65%, dysmegakaryopoiesis being the most common. So, HIV infection should be considered in the differential diagnosis of patients with secondary myelodysplasia or unexplained bone marrow changes.

   Acknowledgment Top

Special thanks to the Institute of Haematology and Transfusion Medicine, Medical College and Hospital, Kolkata, and School of Tropical Medicine, Kolkata, for technical assistance.

   References Top

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19.Guillemain C, George F, Courcoul M, Dhiver C, Brunet C, Spire B, et al. Monoblastic leukemia in an HIV infected patient: Absence of viral expression in RNA blasts. Am J Hematol 1996;52:47-52.  Back to cited text no. 19
20.Kaczmarski RS, Davison F, Blair E, Sutherland S, Moxham J, McManus T, et al. Detection of HIV in haemopoietic progenitors. Br J Hematol 1992;82:764-9.  Back to cited text no. 20
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22.Katsarou O, Terpos E, Patsouris E, Peristeris P, Viniou N, Kapsimali V, et al. Myelodysplastic features in patients with long-term HIV infection and haemophilia. Haemophilia 2001;7:47-52.  Back to cited text no. 22
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24.Møller T, Hasselbalch HC. Hematological changes associated with HIV infection. Ugeskr Laeger 1993;155:1442-6.  Back to cited text no. 24

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Arindam Pande
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DOI: 10.4103/0377-4929.85089

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]

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