Viral and Bacterial Illnesses Associated with Marked Hematologic Sequelae

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Parvovirus

Parvovirus B19 has a peculiar predilection for rapidly growing cells, particularly red cell precursors in the bone marrow. It has a preference for the red cell precursors because it uses P antigen as a receptor. This viral infection is associated with a transient erythroblastopenic crisis, particularly in individuals with an underlying hemolytic disorder. In addition, it can produce thrombocytopenia, neutropenia, and a hemophagocytic syndrome. In immunocompromised individuals, parvovirus B19 infection can produce prolonged aplasia.

Epstein-Barr Virus

Epstein-Barr virus (EBV) infection is associated with the following hematologic manifestations:

• Atypical lymphocytosis

• Acquired immune hemolytic anemia

• Agranulocytosis

• Aplastic anemia

• Lymphadenopathy and splenomegaly

• Immune thrombocytopenia.

EBV infection also has immunologic and oncologic associations (see Chapter 13):

• X-linked lymphoproliferative syndrome associated with fatal EBV infection, acquired hypogammaglobulinemia, and lymphoma

• Clonal T-cell proliferations

• Hemophagocytic syndrome

• Endemic form of Burkitt's lymphoma in Africa.

Human Immunodeficiency Virus

The main pathophysiology of human immunodeficiency virus (HIV) infection is a constant decline in CD4+ lymphocytes, leading to immune collapse and death. The other bone marrow cell lines also decline in concert with CD4+ cell numbers as HIV disease (acquired immunodeficiency syndrome [AIDS]) progresses. HIV infection has the hematologic manifestations discussed next.

Thrombocytopenia

Thrombocytopenia occurs in about 40% of patients with AIDS. Initially, the clinical findings resemble those of immune thrombocytopenic purpura (ITP). Some degree of splenomegaly is common and the platelet-associated antibodies are often in the form of immune complexes that may contain antibodies with anti-HIV specificity. Megakaryocytes are normal or increased, and production of platelets is reduced in the bone marrow. Thrombotic thrombocytopenic purpura (TTP) is also associated with HIV disease. This occurs in advanced AIDS.

Anemia and Neutropenia

HIV-infected individuals develop progressive cytopenia as immunosuppression advances. Anemia occurs in approximately 70-80% of patients and neutropenia in 50%. Cytopenias in advanced HIV disease are often of complex etiology and include the following:

• A production defect appears to be most common.

• Antibody and immune complexes associated with red and white cell surfaces may contribute. Up to 40% have erythrocyte-associated antibodies. Specific antibodies against i and U antigens have occasionally been noted. About 70% of patients with AIDS have neutrophil-associated antibodies.

The pathogenesis of the hematologic disorders includes:

• Infections: Myelosuppression is frequently caused by involvement of the bone marrow by infecting organisms (e.g., mycobacteria, cytomegalovirus [CMV], parvovirus, fungi, and, rarely, Pneumocystis carinii).

• Neoplasms: Non-Hodgkin lymphoma (NHL) in AIDS patients is associated with infiltration of the bone marrow in up to 30% of cases. It is particularly prominent in the small noncleaved histologic subtype of NHL.

• Medications: Widely used antiviral agents in AIDS patients are myelotoxic; for example, zidovudine (AZT) causes anemia in approximately 29% of patients. Ganciclovir and trimethoprim/sulfamethoxazole or pyrimethamine/sulfadi-azine cause neutropenia. In general, bone marrow suppression is related to the dosage and to the stage of HIV disease. Importantly, the other nucleoside analogues of anti-HIV compounds (dideoxycytidine [ddC], dideoxyinosine [ddI], stavudine [d4T], or lamivudine [3TC]) are usually not associated with significant myelotoxicity.

• Nutrition: Poor intake is common in advanced HIV disease and is occasionally accompanied by poor absorption. Vitamin B12 levels may be significantly decreased in HIV infection although vitamin B12 is not effective in treatment. The reduction in serum vitamin B12 levels is due to vitamin B12 malabsorption and abnormalities in vitamin B12-binding proteins.

Coagulation Abnormalities

The following abnormalities occur:

• Dysregulation of immunoglobulin production may affect the coagulation cascade. The dysregulation of immunoglobulin production may also occasionally result in beneficial effects, as in the resolution of anti-factor VIII antibodies in HIV-infected hemophiliacs.

• Lupus-like anticoagulant (antiphospholipid antibodies) or anticardiolipin antibodies occur in 82% of patients. This is not associated with thrombosis in AIDS patients.

• Thrombosis may occur secondary to protein S deficiency. Low levels of protein S occur in 73% of patients.

Role of Hematopoietic Growth Factors in AIDS

• rHuEPO results in a significant improvement in hematocrit and reduces transfusion requirements while the patient is receiving zidovudine. rHuEPO therapy should be initiated if the erythropoietin threshold is less than 500 IU/L.

• G-CSF in a dose of 5 |g/kg/day SC is the most widely used growth factor in neutropenia.

• Granulocytic-macrophage colony-stimulating factor (GM-CSF) improves neu-trophil counts in drug-induced neutropenia. The effects of GM-CSF are seen within 24-48 hours with relatively low doses of GM-CSF (250 |g/m2 3 x week).

• Interleukin-3 (IL-3) given in doses of 0.5-5 mg/kg/day increases neutrophil counts.

Cancers in Children with HIV Infection

Malignancies in children with HIV infection are not as common as those in adults.

Table 5-2 lists AIDS-related neoplasms in adults, and Table 5-3 lists AIDS-related neoplasms in children with HIV infection in the order of frequency.

Table 5-2. AIDS-Related Neoplasms in Adults

Kaposi sarcoma Non-Hodgkin lymphoma Anogenital cancers Cervical cancer

Epithelioid anal cancer Hodgkin disease Leiomyosarcoma Testicular tumors Conjunctival tumors Melanoma Renal tumors Skin cancer Basal cell carcinoma Squamous cell carcinoma Lung cancer

Adenocarcinoma

Table 5-3. AIDS-Related Neoplasms in Children

Non-Hodgkin lymphoma

Burkitt lymphoma (B-cell, small noncleaved) Immunoblastic lymphoma (B-cell, large cell) Central nervous system lymphomas Mucosa-associated lymphoid tissue (MALT) type Leiomyosarcoma and leiomyoma Kaposi's sarcoma Leukemias

Non-Hodgkin lymphoma (NHL)

NHL is the most common malignancy secondary to HIV infection in children. It is usually of B-cell origin as in Burkitt (small noncleaved cell) or immunoblastic (large cell) NHL. The mean age of presentation of malignancy in congenitally transmitted disease is 35 months, with a range of 6-62 months. In transfusion-transmitted disease, the latency from the time of HIV seroconversion to the onset of lymphoma is 22-88 months. The CD4 lymphocyte count is less than 50/mm3 at the time of diagnosis of the malignancy.

The presenting manifestations include:

• Extranodal manifestations (e.g., hepatomegaly, jaundice, abdominal distention, bone marrow involvement, or central nervous system [CNS] symptoms).

Some patients will already have had lymphoproliferative diseases such as lym-phocytic interstitial pneumonitis or pulmonary lymphoid hyperplasia. These children usually have advanced (stage III or IV) disease at the time of presentation.

Central nervous system lymphomas

Children with CNS lymphomas present with developmental delays or loss of developmental milestones and encephalopathy (dementia, cranial nerve palsies, seizures, or hemiparesis).

The differential diagnosis includes infections such as toxoplasmosis, cryptococco-sis, or tuberculosis. Contrast-enhanced computed tomography (CT) studies of the brain show hyperdense mass lesions that are usually multicentric or periventricular. CNS lymphomas in AIDS are fast growing and often have central necrosis and a "rim of enhancement" as in an infectious lesion. A stereotactic biopsy will give a definitive diagnosis.

Treatment of HIV infection-related lymphomas. Treatment consists of standard protocols as described in Chapter 16 on non-Hodgkin lymphoma. Treatment of CNS lymphomas is more difficult. Intrathecal therapy is indicated even for those without evidence of meningeal or mass lesions at diagnosis of NHL. Radiation therapy may be a helpful adjunct for CNS involvement.

The following are more favorable prognostic features in NHL secondary to AIDS:

• CD4 lymphocyte count greater than 100/mm3

• Normal serum LDH level

• No prior AIDS-related symptoms

Proliferative lesions of mucosa-associated lymphoid tissue

Mucosa-associated lymphoid tissue (MALT) shows reactive lymphoid follicles with prominent marginal zones containing centrocyte-like cells, lymphocytic infiltration of the epithelium (lymphoepithelial lesion), and the presence of plasma cells under the surface epithelium. These lesions may be associated with the mucosa of the gastrointestinal tract, Waldeyer ring, salivary glands, respiratory tract, thyroid, and thymus. Proliferative lesions of MALT can be benign or malignant (such as lymphomas).

The proliferative lesions arising from MALT form a spectrum or a continuum extending from reactive to neoplastic lesions. The neoplastic lesions are usually low grade but may progress into high-grade MALT lymphomas (Table 5-4). MALT lymphomas characteristically remain localized, but if dissemination occurs, they are usually confined to the regional lymph nodes and other MALT sites. MALT lesions represent a category of pediatric HIV-associated disease that may arise from a combination of viral etiologies, including HIV, EBV, and CMV.

Treatment of low-grade MALT lymphoma involves:

• a-Interferon: 1,000,000 units/m2 SC three times a week; continue until regression of disease or severe toxicity occurs.

• Rituxan (monoclonal antibody-anti-CD20): 375 mg/m2 IV weekly for 4 weeks; courses may be repeated as clinically indicated.

Table 5-4. Spectrum of Systemic Lymphoproliferation in Children with AIDS

Follicular hyperplasia (lymph nodes, gastrointestinal tract) Lymphoid follicles/nodular (liver, thymus)

Thymitis and multilocular thymic cyst PLH/LIP complex, typical and atypical

Polyclonal polymorphic B-cell lymphoproliferative disorder

Myoepithelial sialoadenitis

Myoepithelial sialoadenitis with lymphoma

MALT lymphoma (involving lungs, tonsils, and salivary glands)

Non-MALT lymphoma (involving nodal and extranodal sites)

Abbreviations: PLH/LIP, pulmonary lymphoid hyperplasia/lymphoid interstitial pneumonitis; MALT, mucosa-associated lymphoid tissue.

From McClain KL, Joshi VV. Cancer in children with HIV infection. Hematol Oncol Clin North Am 1996;10:1189, with permission.

Some patients may not require any treatment because of the indolent nature of the disease.

Leiomyosarcomas and leiomyomas

Malignant or benign smooth muscle tumors, leiomyosarcoma (LS) and leiomyoma (LM), are the second most common type of tumor in children with HIV infection. The incidence in HIV patients is 4.8% (in non-HIV children, it is 2 per million). The most common sites of presentation are the lungs, spleen, and gastrointestinal tract. Patients with endobronchial LM or LS often have multiple nodules in the pulmonary parenchyma. Bloody diarrhea, abdominal pain, or signs of obstruction may signal intraluminal bowel lesions. These tumors are clearly associated with EBV infection. In situ hybridization and quantitative polymerase chain reaction studies of LM and LS demonstrated that high copy numbers of EBV are present in every tumor cell. The EBV receptor (CD21/C3d) is present on tumor tissue at very high concentrations, but is present at lower concentrations in normal smooth muscle or control leiomy-omas/leiomyosarcomas that had no EBV DNA in them. In AIDS patients, the EBV receptor may be unregulated, allowing EBV to enter the muscle cells and cause their transformation.

Treatment involves:

Chemotherapy, including doxorubicin or a-interferon

• Radiotherapy

• Complete surgical resection prior to chemotherapy, where feasible. Despite surgery and chemotherapy, the disease tends to recur.

Kaposi sarcoma

Kaposi sarcoma (KS) is rare in children and constitutes the third most common malignancy in pediatric AIDS patients; it occurs in 25% of adults with AIDS. KS occurs only in those HIV-infected children who were born to mothers with HIV. The lymphadenopathic form of KS is seen mostly in Haitian and African children and may represent the epidemic form of KS unrelated to AIDS. The cutaneous form is a true indicator of the disease related to AIDS. Visceral involvement has not been pathologically documented in children with AIDS.

Leukemias

Almost all leukemias are of B-cell origin. They represent the fourth most common malignancy in children with AIDS. The clinical presentation and biologic features are similar to those found in non-HIV children.

Treatment involves chemotherapy designed for B-cell leukemias and lymphomas.

Miscellaneous tumors

There is no increase of Hodgkin disease in children with AIDS as compared to adult patients. Children with AIDS rarely develop hepatoblastoma, embryonal rhab-domyosarcoma, fibrosarcoma, and papillary carcinoma of the thyroid. The occurrence of these tumors is probably unrelated to the HIV infection.

Torch Infections

This is a group of congenital infections including toxoplasma, rubella, CMV, herpes simplex virus (HSV), and syphilis. They can all cause neonatal anemia, jaundice, thrombocytopenia, and hepatosplenomegaly.

Bordetella Pertussis

This organism causes pertussis (whooping cough). It is invariably associated with marked lymphocytosis (>25,000/mm3) in early stages of infection.

Acute Infectious Lymphocytosis

Acute infectious lymphocytosis is caused by a coxsackievirus and is a rare benign, self-limiting childhood condition. It is associated with a low-grade fever, diarrhea, and marked lymphocytosis (50,000/mm3). Lymphocytes are mainly CD4 T cells. The condition resolves in 2-3 weeks without treatment (page 242).

Bartonellosis

Bartonellosis is caused by a gram-negative bacillus Bartonella bacilliformis confined to the mountain valleys of the Andes. The vector is a local sand fly. Infection from this organism causes a fatal syndrome of severe hemolytic anemia with fever (Oroya fever). Another species of Bartonella, B. henselae, causes "cat scratch fever." It is associated with a regional (following a scratch by a cat) lymphadenitis. Thrombocytopenia may occur in this condition.

Tuberculosis

Tuberculosis is caused by Mycobacterium tuberculosis. Hematologic manifestations include leukemoid reaction mimicking CML, monocytosis, and rarely pancytopenia.

Leptospirosis (Weil Disease)

This disease is caused by Leptospira icterohaemorrhagiae. A coagulopathy occurs that is complex and can be corrected with vitamin K administration. Thrombocytopenia commonly occurs but DIC is rare.

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