Hematologic Manifestations of HIV/AIDS Parth S
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HIV Curriculum for the Health Professional Hematologic Manifestations of HIV/AIDS Parth S. Mehta, MD Objectives (lowered levels of platelets), or any combination of these three. The causes of these conditions are varied and are 1. Review the physiology of normal hematopoiesis. not fully understood. Evidence shows that HIV infects the 2. Review the pathogenesis of the hematological progenitor cells in the bone marrow, the hematopoietic manifestations of human immunodeficiency virus stem cells (HSCs), and causes abnormal function. When (HIV). HSCs cannot produce adequate hematopoietic growth 3. Identify the clinical manifestations of altered factors (the substances that stimulate the production of hematopoiesis resulting from HIV infection. blood cells in the bone marrow), decreased production of 4. Discuss relevant laboratory findings in anemia, blood cells occurs. Also, antiretroviral treatment for HIV neutropenia, and thrombocytopenia. infection, opportunistic infections and their treatment, 5. Establish care guidelines for children with HIV and chemotherapy for treatment of HIV-associated infection and altered hematopoiesis resulting in malignancies also cause altered hematopoiesis, which can anemia, neutropenia, and thrombocytopenia. contribute to the problem. Key Points This chapter reviews normal hematopoiesis and the 1. Altered hematopoiesis in patients with HIV can clinical manifestations of children with altered hemato- affect all cell lines (white blood cells, red blood cells, poiesis, followed by a discussion of the causes of the and platelets). different manifestations of altered hematopoiesis and 2. Anemia is multifactorial in HIV infection, their management and treatment. with causes including opportunistic infection, myelosuppressive drugs, nutritional deficiencies, Normal Hematopoiesis and the direct effects of HIV on bone marrow To understand abnormal blood cell production, one must progenitors and stromal elements. know how normal hematopoiesis occurs. To have normal 3. The primary risk for children with HIV/AIDS with hematopoiesis, the HSC must be present because it is neutropenia is the risk for overwhelming and life- the cell from which all blood cells will be derived during a threatening infection. person’s lifetime. 4. The primary cause of thrombocytopenia in children with HIV/AIDS is an idiopathic thrombocytopenic HSCs are situated in the bone marrow, spleen, liver, and purpura syndrome secondary to a dysregulated peripheral blood. HSCs in the bone marrow produce immune system as a result of HIV infection. almost all blood cells, whereas the other sites assist in times of undue stress. Only about 5% of the HSCs in the Overview bone marrow are functioning at any one time, yet they Altered hematopoiesis (blood cell production) occurs in can maintain the hematopoietic system for the lifetime of patients with HIV infection. This change affects all three the person. cell lines (red blood cells, white blood cells, and platelets) that come from stem cells in the marrow. Consequently, In addition to the stem cell, supportive cells, called HIV-infected children may suffer from anemia (lowered stromal cells, must be present for normal hematopoiesis levels of red cells), neutropenia (lowered levels of white to occur. T lymphocytes, macrophages, endothelial blood cells called neutrophils), thrombocytopenia cells, and fibroblasts help to produce the hematopoietic 222 222 Hematologic Manifestations of HIV/AIDS growth factors that are needed for production and • Headaches, dizziness differentiation of normal white blood cells in the bone • Tachycardia, heart murmur marrow. Erythropoietin, produced in the kidney, and • Cold or discolored extremities thrombopoietin, produced in the liver, are necessary • Glossitis for proliferation and production of red blood cells and • Nail bed deformities platelets, respectively. The cells of the bone marrow grow in clumps known as colonies. Cells differentiate from the Clinical Presentation of a Child with Neutropenia earliest progenitor cells, the HSCs, to progenitor cells of • May be asymptomatic the different cell lineages, and these colonies then further • Fever mature toward becoming red blood cells, white blood cells • Skin ulcerations or lesions (neutrophils, monocytes), and platelets. The progenitors • Tachypnea, cough, wheezing, rales of the red blood cells are in the erythroid lineage, whereas • Stomatitis, dysphagia the white blood cells are derived from the granulocyte- • Abdominal pain, diarrhea macrophage colonies of progenitor cells, and finally • Perirectal pain or fissure the megakaryocytes of the bone marrow give rise to circulating platelets. Clinical Presentation of a Child with Thrombocytopenia • Bruising, petechiae, purpura Alterations in hematopoiesis can lead to abnormalities • Epistaxis in red cell, white cell, and platelet count in the peripheral • Gingival bleeding blood. A decrease in the number of white cells is called • Hematuria leukopenia, and a decrease in the number of platelets • Hematochezia is called thrombocytopenia. A decrease in the white blood cells known as neutrophils is called neutropenia. Pathogenesis of Hematological Anemia is a decrease in red cell number, hemoglobin, or Manifestations of HIV Infection hematocrit. Anemia is further classified by the size of the Abnormalities of Bone Marrow red cells in the peripheral blood as microcytic (smaller Bone marrow in HIV-infected children undergoes than normal), normocytic (normal), or macrocytic (larger changes. The most common changes seen in morphology than normal). of the marrow architecture include decreased cellularity Clinical Manifestations of Altered and myelodysplasia (abnormal change of the cellular structure) affecting the cells of the erythroid lineage Hematopoiesis and the megakaryocytes. Dysplastic changes of the Children with alterations in hematopoiesis should have granulocyte-macrophage lineage with arrest of matura- a comprehensive patient history, physical examination, tion can occur in the marrow of children with HIV complete blood count, and liver function tests. Children infection. with anemia should also have a reticulocyte count, lactate dehydrogenase test, and Coombs’ test. A peripheral These changes impair growth of bone marrow cultures in smear should be examined because it provides a great vitro from patients with HIV infection. There is a decrease deal of information on cell morphology and can give in the number of HSCs in the bone marrow of patients clues to the cause of the alteration in hematopoiesis. with HIV infection. Furthermore, HIV can directly infect Bone marrow aspiration and biopsy may be necessary the bone marrow stromal cells, leading to aberrations to determine the cause. The following sections review in their function. This development in turn leads to the signs and symptoms of anemia, neutropenia, and abnormal maturation of the different bone marrow thrombocytopenia. cell lineages and may explain the preceding structural changes. Clinical Presentation of a Child with Anemia • Pale conjunctivae or palmar creases, jaundice One can also observe drug-induced suppression of bone • Fatigue or irritability marrow in children with HIV infection. The most common • Decreased ability to concentrate cause is the antiretroviral drug zidovudine (AZT). This 223 HIV Curriculum for the Health Professional drug inhibits the colony formation of stem cells as well as multifactorial, and managing anemia can involve a variety erythroid and granulocyte-macrophage progenitor cells. of modalities (Table 1). HIV infection and its direct Other drugs can affect the bone marrow, and drugs used effects on HSCs and stromal elements can lead to anemia. to treat opportunistic infections in HIV-infected children Opportunistic infection and myelosuppressive drugs suppress the bone marrow. Acyclovir and ganciclovir used might also cause anemia. Furthermore, children with HIV in the prevention and treatment of herpes simplex virus infection often have abnormally low levels of iron and infection and cytomegalovirus (CMV) infection can both possibly cobalamin (vitamin B12), substances necessary suppress the marrow. Trimethoprim-sulfamethoxazole for normal red blood cell production. Iron deficiency, the used to prevent and treat Pneumocystis jirovecii most common cause of anemia worldwide, is a frequent pneumonia also suppresses the bone marrow. Finally, comorbid and treatable condition in children with HIV opportunistic infections can cause marrow suppression, infection. The association of vitamin B12 is less clear: particularly CMV, parvovirus B19, and Mycobacterium one study showed serum B12 levels to be low in only avium complex (MAC) infections. 20% of adults with HIV infection. Anemia due to iron deficiency is microcytic, and that due to B12 deficiency One should consider the diagnosis of marrow suppression has associated changes in the neutrophils known as in any child with HIV infection when the blood count megaloblastic change. demonstrates a decrease in white cell (leukopenia), platelet (thrombocytopenia), or reticulocyte (immature Another well-known cause of anemia is pure red cell red cells) count. One should consider the diagnosis of aplasia, caused by infection with parvovirus B19, and bone marrow dysfunction especially if there are decreases should be considered in children with HIV infection in more than one cell line. Many other factors can cause that have isolated anemia. Other marrow-suppressive anemia, which when present alone is not as concerning infections