Page 2543 - Hematology_ Basic Principles and Practice ( PDFDrive )

2266 Part XIII Consultative Hematology

period of symptomatic conditions which may or may not fulfill cri- impaired as a result of infection. However, in vivo infection of pro-
teria for classification as symptomatic AIDS (see Table 157.2). The genitor cells rarely if ever occurs. Progenitor populations such as those
acute retroviral syndrome occurs in approximately 50% to 80% of yielding megakaryocytes or monocytes can be infected. Recent studies
newly infected individuals. The onset of symptoms occurs 1 to 3 have documented infection and depletion of intermediate myeloid
weeks (range 5 days to 3 months) after primary infection. Symptoms precursors, including the common myeloid precursor, granulocyte-
last from 1 to 2 weeks and can include significant fatigue, headache, monocyte precursor, and even the megakaryocyte-erythroid precursor
malaise, fever as high as 40°C, sore throat, and myalgias. A morbil- (MEP) despite the failure of MEP to express CD4.
liform rash can be observed in 40% to 50% of patients, with general- HIV infection leads to hematopoietic inhibition in vivo by deplet-
ized lymphadenopathy occurring toward the end of the acute illness. ing myeloid and erythroid colony-forming precursor activity. This
Symptoms are similar to those observed in other viral syndromes such activity may be caused by an indirect mechanism rather than direct
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as mononucleosis. Laboratory findings may include lymphocytosis, infection of CD34 cells. The presence of messenger RNA for and
occasional neutropenia, and mild thrombocytopenia. Most symptoms cell surface expression of HIV receptors CD4 and the chemokine
subside within a month. However, lymphadenopathy may persist in receptors CXCR-4 and CCR-5 have been demonstrated in fraction-
over 50% of patients and is termed the persistent generalized lymph- ated cells representing multiple stages of hematopoietic development
adenopathy (PGL) syndrome of HIV infection. Patients may be (see box on Hematologic Manifestations of Human Immunodefi-
serologically negative during the acute retroviral syndrome and if ciency Virus/Acquired Immunodeficiency Syndrome). Productive
there is high clinical suspicion, patients should be tested by reverse infection by HIV via these receptors is observed with the notable
transcriptase-polymerase chain reaction (PCR) for the presence of exception of stem cells, in which case the presence of CD4, CXCR-4,
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plasma virus RNA, which is frequently present in high levels. and CCR-5 is insufficient for infection. Although direct infection of
With resolution of the acute retroviral syndrome, patients may stem cells does not occur, alterations in stem cell number and func-
enter a phase of asymptomatic infection with lower levels of viral tion have been documented. HIV replication in the bone marrow
replication as determined by their plasma viral load with serologic microenvironment is believed to be the essential component causing
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evidence of infection. Without antiretroviral therapy, this phase may decreased hematopoietic cell production in HIV infection. The exact
persist for nearly a decade. Progression can be variable and is deter- mechanism by which the microenvironment induces these alterations
mined by a variety of viral, immunologic, and host factors. Coinfec- is unknown. Mononuclear-macrophage cells can develop productive
tions with other viruses such a hepatitis B and C, cytomegalovirus HIV infection and the resultant aberrant release of cytokines, such
(CMV), Epstein-Barr virus (EBV), and herpes viruses can impose as TGF-β, tumor necrosis factor-α (TNF-α), and IL-1 can contribute
additional immunologic stress leading to accelerated progression of to the suppression of hematopoiesis. TNF-α is a potent mediator of
disease and additional AIDS-defining clinical conditions. Infection inflammation and host response to infectious diseases, with pleiotro-
with human herpes virus 8 is associated with the well-characterized pic effects such as tissue damage, caloric wasting, and impairment of
AIDS-defining complications of Kaposi sarcoma, primary effusion hematopoiesis. It has been observed that HIV suppresses hematopoi-
lymphoma, and multicentric Castleman disease. EBV infection may esis through induction of TNF-α. TNF-binding protein has been
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contribute to the high incidence of lymphoma, including central shown to reverse in vitro hematopoietic defects. The relationship of
nervous system lymphomas, observed in the severely immunosup- virus replication to inducing the hematopoietic defects is most readily
pressed HIV patients. apparent in the clinical changes seen when patients initiate potent
A distinct subset of HIV-1 infected patients has a significantly antiretroviral therapy. When patients begin HAART, an increase in
slower rate of HIV disease progression and maintains good immuno- white blood cells (WBCs), polymorphonuclear neutrophils, and
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logic function for extended periods without antiretroviral therapy. platelets in addition to an increase in CD4 T cells occurs as plasma
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These individuals, termed long-term nonprogressors, are a popula- HIV RNA levels decline. T-cell kinetics studies have demonstrated
tion of significant clinical and research interest. They include patients a markedly shortened half-life of peripheral blood T cells from
who are heterozygous for the delta 32 deletion in the CCR5 chemo- approximately 82 days to 23 days. Initiation of antiretroviral therapy
kine coreceptors for HIV infection. This mutation is estimated to does not improve lymphocyte half-life. The increase in T-cell numbers
occur in 15% of white people. Patients with human leukocyte antigen in the peripheral blood of patients treated with HAART appears to
(HLA)-B27 and HLA-B57 also appear to have better control of HIV be a result of improved production, which in turn may be caused by
viral replication and slower disease progression. This may result from one of several mechanisms: expansion or redistribution of existing
an inability of these patients’ T regulatory lymphocytes to suppress subsets of cells or de novo production of T cells from the thymus.
CD8–cytotoxic lymphocyte HIV-specific responses. The increase in T cells following initiation of HAART is biphasic. In
In the absence of antiretroviral therapy, HIV infected patients
develop progressive immunodeficiency with the development of
opportunistic infections, central and peripheral neurologic symptoms,
HIV-associated malignancies, fatigue, weight loss, and a general BOX 157.1 Hematologic Manifestations of Human Immunodeficiency
wasting syndrome (see Table 157.2). Virus/Acquired Immunodeficiency Syndrome
In addition to the CD T cell lymphopenia, which is the hallmark of HIV
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HEMATOLOGIC AND BONE MARROW ABNORMALITIES infection, other cytopenias are the most common manifestations in
these individuals. During the course of the disease thrombocytopenia
IN HIV-1 INFECTION and neutropenia occurs at a rate of 40% and 50% respectively. Anemia
can occur in up to 70%. Direct infection of the hematopoietic stem
cells by HIV does not account for the degree of cytopenias seen. In
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The hallmark of HIV infection is the CD4 lymphopenia. However, fact, in vivo infection of the stem cells by HIV occurs rarely if ever.
during the course of the disease about 70% to 80% of patients with However, HIV infection leads to hematopoietic inhibition in vivo by
HIV/AIDS will develop anemia, 50% will develop neutropenia, and depleting granulocytic, monocytic, erythroid, and megakaryocytic
40% will develop thrombocytopenia. The presence of cytopenias in colony forming units. Progenitor populations such as those yielding
megakaryocytes and monocytes are infectable. Macrophages in the
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addition to the CD4 T lymphopenia of HIV disease has long sug- bone marrow stroma can develop productive HIV infection with the
gested that the suppressive effects of HIV on the hematopoietic resultant release of cytokines (TGF-β, TNF-α, IL-1) that contribute to
compartment are far more broadly based than just a select subset of suppression of hematopoiesis. Importantly, there are etiologies that are
T cells. A number of studies have assessed the bone marrow micro- more specific to causing anemia, thrombocytopenia and neutropenia
environment, the cytokine milieu, and the number and the function respectively. Hence these entities are discussed separately.
of primitive hematopoietic elements in HIV disease. A low fraction
of progenitor cells can be infected ex vivo by HIV under some condi- HIV, Human immunodeficiency virus; IL-1, interleukin 1; TGF-β, transforming
growth factor β; TNF-α, tumor necrotic factor α.
tions. The growth of these few cells infected by HIV may not be