Bone marrow changes

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Myelodysplasia

Abnormalities in the bone marrow are very common at all stages of HIV disease (Table 23.2), increasing in frequency as the disease progresses. The most common abnormal finding is of dysplasia affecting one or more of the cell lines. In general, the more advanced the disease, the more marked the dysplasia, and, although erythroid dysplasia is the most common finding, being recognized in over 50% of HIV-infected patients, abnormal granulocytic and megakaryocytic development is encountered in approximately one-third of patients.

Dyserythropoiesis may be manifest by florid megaloblastic change. This is unrelated to serum cobalamin and folate levels, or to drug therapy with zidovudine or folate antagonists, although these drugs may accentuate it. Erythroblasts are often bi- or multinucleated, with an irregular nuclear outline and basophilic stippling (Figure 23.2). Abnormal sideroblasts including ringed forms may be present. The frequently observed reticuloendo-thelial iron block is likely to be secondary to concurrent infection or chronic disease. Erythropoiesis appears disorganized on trephine biopsy with poorly formed erythroid islands.

Dysplastic features in megakaryocytes are common, occurring in over one-third of marrows and including nuclear hypo-lobulation and micromegakaryocytes (Figure 23.3). On trephine biopsy, megakaryocyte hyperplasia and clustering may be very pronounced. Increased numbers of naked megakaryocytic nuclei are a consistent feature.

Granulocytic dysplasia may be apparent at all stages of maturation, with giant metamyelocytes, nuclear abnormalities including detached nuclear fragments and Pelger cells reflecting

Table 23.2 Features of bone marrow in HIV disease.

Dysplasia

70% of marrows show some dysplastic features

Erythroid dysplasia 60%

Granulocytic dysplasia 30%

Megakaryocytic dysplasia 40%

Cellularity

Increased in over 50%

Hypocellular 15%

Fibrosis

Seen in 20-50% of trephines and may make aspiration

difficult

Reticuloendothelial iron block

Common manifestation of chronic disease

Histiocytes

Increased and may show haemophagocytosis

Plasma cells

Increased and may be atypical

Opportunistic infections

Culture or examination of slides may show acid-fast

bacilli (AFB), leishmania, histoplasma,

pneumocystis, cryptococcus

Granulomas

Seen in infection with AFB and cryptococcus

Lymphoid aggregates

Reactive nodules

AIDS-related lymphoma (ARL)

20% of patients with ARL have bone marrow

involvement

Bone Marrow Dysplasia And Hiv

Figure 23.2 Erythroid dysplasia in HIV disease.

Bone Marrow And Dysplasia

Figure 23.4 Bone marrow trephine biopsy in HIV disease, showing hypercellularity and increased numbers of dysplastic megakaryocytes.

Figure 23.2 Erythroid dysplasia in HIV disease.

Figure 23.4 Bone marrow trephine biopsy in HIV disease, showing hypercellularity and increased numbers of dysplastic megakaryocytes.

Dysplastic Megakaryocytes
Figure 23.3 Dysplastic megakaryocytes in HIV disease.

dysfunctional nuclear maturation. On trephine biopsy, the atypical localization of immature precursors, a feature that has been highlighted in primary myelodysplastic syndrome, is sometimes observed in HIV marrows. Apoptosis is increased. In non-HIV patients, granulocytic dysplasia may precede acute leukaemia. Although several HIV antibody-positive patients with acute myeloid leukaemia have been described, the role of myelodys-plasia in the evolution of acute leukaemia in HIV disease is uncertain. Its rarity and the failure to detect chromosomal abnormalities in patients with marked dysplastic changes suggest that myelodysplasia in the setting of HIV disease is not generally a pre-leukaemic state, thus differing from the classic myelodysplastic syndrome. The term 'HIV-related myelodysplasia' has been coined to describe the changes in HIV disease.

Ultrastructure studies of bone marrow cells from patients infected with HIV have shown abnormalities in erythroid cells, marrow granulocytes, plasma cells and stromal cells, which were attributed to a direct effect of HIV infection. No definite viral particles were detected at electron microscopy level, although the presence of incomplete virus particles was not excluded. The abnormalities in stromal cells lend credence to the hypo-

Figure 23.5 Bone marrow trephine biopsy in HIV disease, showing increased fibrosis.

thesis that disturbances in the microenvironmental regulation of haemopoiesis may contribute to cytopenias.

Cellularity

Marrow from HIV-infected patients is sometimes difficult to aspirate and the trails are of decreased cellularity. The true marrow cellularity is better appreciated on trephine biopsy, which is hypercellular in a majority of patients (Figure 23.4). The difficulty in aspiration may in part be due to the increased reticulin fibrosis seen especially in hypercellular marrows (Figure 23.5). Hypercellularity of the marrow in the face of peripheral cytopenia is a very common finding in HIV disease and is likely to reflect myeloid dysplasia and ineffective haemopoiesis. Indeed, there is a correlation between observed marrow dysplastic changes and the peripheral blood findings of anaemia and leucopenia.

Red cell hypoplasia has been described in patients with HIV disease and may be associated with infection with B19 parvovirus and disseminated Mycobacterium avium intracellulare. Severe erythroid hypoplasia has also been described in patients receiving therapy with zidovudine.

Gelatinous transformation (serous fat atrophy) is common in marrow from HIV patients and has been described previously in patients with severe malnutrition and weight loss.

Histiocytes

Increased numbers of histiocytes are often seen in the bone marrow and in many patients haemophagocytosis is striking. Reactive haemophagocytosis has been described in patients suffering from a wide variety of viral, bacterial, fungal and parasitic infections and is more common in immunosuppressed patients. In many of the patients with HIV infection who show increased numbers of marrow histiocytes, there is no obvious infective cause and it is likely that HIV itself is the trigger to histiocyte proliferation and phagocytosis, probably by initiation of cytokine production, resulting in macrophage stimulation. It is likely that as a result of HIV infection the marrow produces a histiocytic reaction, which varies from increased numbers of histiocytes to a full-blown haemophagocytic syndrome with severe pancytopenia.

Plasma cells

Plasma cells are often strikingly increased in the marrow of HIV-infected patients. They may represent a physiological response to antigenic stimulation by viruses or other infective agents, or may be secondary to dysregulated B-cell proliferation due to HIV. The marrow plasmacytosis is not confined to those patients with advanced HIV disease in whom opportunistic infections could be implicated, but is seen also in patients at an early stage who have no concurrent infections. The plasma cells are often morphologically abnormal and may appear in clusters. A polyclonal increase in gammaglobulins occurs in most HIV patients. Paraproteinaemia occurs in approximately 9% of homosexual HIV antibody-positive men without AIDS. This is much higher than the incidence of paraproteins in healthy people of similar age and may result either from changes in T-cell regulation or from the activation of B lymphocytes directly infected by HIV. The prognostic significance of paraproteinaemia in HIV antibody-positive patients is unknown. It does not appear to be more common in patients developing non-Hodgkin's lymphoma (NHL), although this also occurs in the setting of clonal B-cell activation. Some of the paraproteins have activity against HIV gag and pol gene products and may represent a vigorous immune response to HIV infection.

Multiple myeloma has been described in a few patients with HIV disease and occurs at a much younger age than in the general population.

Lymphoid aggregates

Lymphoid aggregates are identified in one-third of trephine biopsies and are likely to be benign manifestations of infection with HIV rather than a response to opportunistic infections or a herald of malignant lymphoma.

Opportunistic infections

Bone marrow examination and culture have a contribution to make to the diagnosis of opportunistic infections. Trephine biopsy may yield histochemical evidence of acid-fast bacilli or fungal organisms (Figure 23.6). Acid-fast bacilli (both Mycobacterium tuberculosis and atypical mycobacteria) may be cultured from the bone marrow of patients with disseminated infection. The bone marrow may be the only site of culture, despite cultur-ing of blood, induced sputum and bronchoalveolar lavage.

Disseminated infection with Leishmania donovani-infantum and Histoplasma capsulatum may be diagnosed on the basis of marrow examination (Figures 23.7, 23.8 and 23.9). Clinically, these infections may be atypical in immunosuppressed patients and serological tests are not always helpful. Marrow aspirate and trephine biopsy material, as well as marrow culture, are useful in the monitoring of response to treatment.

Donovan Bodies Macrophages
Figure 23.6 Acid-fast bacilli in trephine biopsy in HIV disease.
Donovan Bodies
Figure 23.7 Leishman-Donovan bodies in macrophage in bone marrow of patient with AIDS.
Histoplasmosis Trephine Biopsy

Figure 23.10 Bone marrow trephine biopsy from a patient with AIDS, showing well-defined granuloma.

Figure 23.8 Leishman-Donovan bodies in trephine biopsy of patient with AIDS.

Haemophagocytosis
Figure 23.9 (a and b) Histoplasma capsulatum in macrophage in bone marrow of patient with AIDS.

Cryptococci and P. carinii have been demonstrated in marrow aspirates and trephine biopsies in patients infected with HIV. Patients in whom opportunistic organisms are present in the bone marrow are profoundly immunosuppressed, as manifest by very low CD4 cell counts. This is in keeping with the observa-

Figure 23.10 Bone marrow trephine biopsy from a patient with AIDS, showing well-defined granuloma.

tion that the major risk factor for infection with Mycobacterium avium-intracellulare is the level of immune dysfunction.

Granulomas (Figure 23.10) may be seen in marrows of patients secondarily infected with mycobacteria and have also been described in cryptococcal infection. Well-formed granulomas are not often associated with atypical mycobacteria and, when associated with M. tuberculosis, caseation is usually conspicuously absent.

Clinical value of bone marrow examination

Examination of the bone marrow is useful in the diagnosis and staging of AIDS-related lymphoma, marrow infiltration being seen in approximately one-fifth of patients; in some patients the marrow represents the initial evidence of lymphoma. Kaposi's sarcoma is extremely rare in the bone marrow.

Culture of marrow aspiration and careful examination of slides from aspirate and trephine biopsy are of value in the diagnosis of opportunistic infections and in the monitoring of treatment.

Immune thrombocytopenia can be suspected on the evidence of plentiful megakaryocytes in the marrow, along with peripheral thrombocytopenia. The value of marrow examination in elucidating the cause of anaemia and leucopenia is less obvious but has occasionally yielded an unexpected diagnosis of disseminated leishmaniasis or histoplasmosis in patients with pancytopenia. The clinical value of bone marrow examination is in:

1 microbiological culture in patients with fever of unknown cause;

2 exclusion or staging of lymphoma;

3 diagnosis of immune thrombocytopenic purpura;

4 elucidation of cytopenias (value less clear).

Lupus anticoagulant

The lupus anticoagulant has been described in patients infected with HIV. This circulating anticoagulant is an IgG or IgM

immunoglobulin, which inhibits in vitro activity of the prothrombin activator complex, thus prolonging the partial thromboplastin time and, to a lesser extent, the prothrombin time.

Thrombotic events in patients with AIDS are rare when compared with patients with the lupus anticoagulant in other settings, where thromboembolic phenomena are common. Patients with a prolonged partial thromboplastin time secondary to a lupus anticoagulant do not appear to be at increased risk of bleeding.

The pathophysiological basis for the development of the lupus anticoagulant in HIV disease is not understood, but an association with active opportunistic infection, especially with P. carinii has been suggested.

Anticardiolipin antibodies have also been described in HIV disease but do not correlate with the presence of a lupus anticoagulant.

Figure 23.11 Diffuse large-cell lymphoma (courtesy of Professor K Henry).

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