Hematological Manifestations Of Systemic Illness

Introduction

A variety of systemic illnesses including acute and chronic infections, neoplastic diseases, connective tissue disorders, and storage diseases are associated with hematological manifestations. The hematologic manifestations are the result of the following mechanisms:
Bone marrow dysfunction:

• Anemia or polycythemia
• Thrombocytopenia or thrombocytosis
• Leukopenia or leukocytosis

Hemolysis

Immune cytopenias

Alterations in hemostasis

• Acquired inhibitors to coagulation factors

• Acquired von Willebrand's disease

• Acquired platelet dysfunction

Alterations in leukocyte function

Chronic Illness

Chronic illnesses such as cancer, connective tissue disease, and chronic infection are associated with anemia. The anemia has the following characteristics:

• Normochromic, normocytic, occasionally microcytic

• Usually mild, characterized by decreased plasma iron and normal or increased reticuloendothelial iron

• Impaired flow of iron from reticuloendothelial cells to the bone marrow

• Decreased sideroblasts in the bone marrow

Treatment involves treating the underlying illness. Iron is of little value because the iron is cleared by the reticuloendothelial system.

Infections

Anemia:

• Chronic infection is associated with the anemia of chronic illness.

• Acute infection, particularly viral infection, can produce transient bone marrow aplasia or selective transient erythrocytopenia.

• Parvovirus B19 infection in people with an underlying hemolytic disorder (such as sickle cell disease, hereditary spherocytosis) can produce a rapid fall in hemoglobin and an erythroblastopenic crisis marked by anemia and reticulocytopenia. There may be associated with neutropenia.

• Many viral and bacterial illnesses may be associated with hemolysis.

White Cell Alterations:

• Viral and bacterial infections can produce leukopenia and neutropenia.

• Neutrophilia with an increased band count and left shift frequently results from bacterial infection.

• Neonates, particularly premature infants, may not develop an increase in white cell count in response to infection.

• Eosinophilia may develop in response to parasitic infections.

Clotting Abnormalities:

• Severe infections, for example, gram-negative sepsis, can produce disseminated intravascular coagulation (DIC).

Thrombocytopenia:
Infection can produce thrombocytopenia through:

• Decreased marrow production

• Immune destruction

• DIC

Viral Illnesses With Marked Hematologic Sequelae

Parvovirus: Parvovirus B19 is associated with transient erythroblastopenic crisis, particularly in individuals with an underlying hemolytic disorder. In addition, it can produce thrombocytopenia, neutropenia, and 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 hemolytic anemia

• Agranulocytosis

• Aplastic anemia

• Lymphadenopathy and splenomegaly

• Immune thrombocytopenia

Epstein-Barr virus infection also has immunologic and oncologic associations:

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

• EBV has also been associated with clonal T-cell proliferations.

• EBV can produce an acquired hemophagocytic syndrome.

• EBV is associated with the 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 following hematologic manifestations:
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 the 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.

Pathogenesis of the hematologic disorders

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).

Neoplasm: Non-Hodgkin's 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, non-cleaved, histologic subtype of NHL.

Medication: 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/sulfadiazine cause neutropenia. In general, bone marrow suppression is related to the dosage and to the stage of HIV disease. Importantly, the other nucleoside analogs of anti-HIV compounds (dideoxycytidine [ddC], dideoxyinosine [ddI], stavudine [d4T], or lamivudine [3TC], are usually not associated with significant myelotoxicity.

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 Acquired Immunodeficiency Syndrome

Erythropoietin: Recombinant human erythropoietin (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.

Neutrophil Growth Factors: Granulocyte colony-stimulating factor (G-CSF) in a dose of 5 mg/kg/day. SC is the most widely used growth factor in neutropenia.

Granulocytic-macrophage colony-stimulating factor (GM-CSF) improves neutrophil counts in drug-induced neutropenia. The effects of GM-CSF are seen within 24-48 hours with relatively low doses of (GM-CSF (0.1 ug/kg/day).

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

Cancers in Children with human immunodeficiency virus infection: Malignancies in children with HIV infection are not as common as those in adults. The following tables show the malignancies occurring in adults and in children with HIV infection in the order of frequency.

Table 1: AIDS-Related Neoplasms in Adults

• Kaposi's Sarcoma

• Non-Hodgkin's lymphoma: Burkitt's lymphoma (B-cell, small non-cleaved), Immunoblastic lymphoma (B-cell, large cell), Central nervous system lymphomas, Mucosa-associated lymphoid tissue (MALT) type

• Leiomyosarcoma and Leiomyoma

• Leukemias

• Anogenital cancers: Cervical cancer, Epitheloid anal cancer

• Hodgkin's disease

• Testicular tumors

• Conjunctival tumors

• Melanoma

• Renal tumors

• Skin cancer: Basal cell carcinoma, Squamous cells carcinoma

• Lung cancer: Adenocarcinoma

Non-Hodgkin's lymphoma (NHL) is the most common malignancy secondary to HIV infection in children. It is usually of B-cell origin as in Burkitt's (small non-cleaved 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 to 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:

• Fever

• Weight loss

Extranodal manifestations (e.g. hepatomegaly, jaundice, abdominal distension, bone marrow involvement, or central nervous system [CNS] symptoms can be seen. Some patients will already have had lymphoproliferative diseases such as lymphocytic 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 delay or loss of developmental milestones

• Encephalopathy (dementia, cranial nerve palsies, seizures, or hemiparesis)

Differential diagnoses include infections such as toxoplasmosis, cryptococcosis, 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 consists of standard protocols as described for Non-Hodgkin's 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 above 100/mm3

• Normal serum LDH level

• No prior AIDS-related symptoms

• Good Karnofsky score (80-100)

Proliferative lesions of mucosa-related lymphoid tissue (MALT): 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's 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 (as shown in the following table). 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 diseases that may arise from a combination of viral etiologies, including HIV, EBV, and CMV.

Table 2: 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)

Treatment consists of Alpha Interferon: 1,000,000 units/m2 SC 3 times a week (continued until regression of the 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). 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 it is present at lower concentrations in normal smooth muscle or controls leiomyomas/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 alpha-interferon

• Radiotherapy

• Complete surgical resection prior to chemotherapy, where feasible

  Despite surgery and chemotherapy, the disease tends to recur.

Kaposi's sarcoma (KS) is rare in children and constitutes the third most 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 in Hodgkin's disease in children with AIDS as compared to adult patients. Children with AIDS rarely develop hepatoblastoma, embryonal rhabdomyosarcoma, fibrosarcoma, and papillary carcinoma of the thyroid. The occurrence of these tumors is probably unrelated to HIV infection.

Bone Marrow Infiltration

The bone marrow may be infiltrated by nonneoplastic disease (storage disease) or neoplastic disease. In storage disease, a diagnosis is established on the basis of the clinical picture, enzyme assays of while cells or cultured fibroblasts, and bone marrow aspiration revealing the characteristic cells of the disorder. The neoplastic disease may arise de novo in the marrow (leukemias) or invade the marrow as metastases from solid tumors (neuroblastoma or rhabdo-myosarcoma). The following table lists the diseases that may infiltrate the marrow.

Table 3: Diseases invading bone marrow

I. Non-neoplastic

II. Neoplastic

• Primary: Leukemia

• Secondary: Neuroblastoma, Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Wilms’ tumor (rarely), Retinoblastoma, Rhabdomyosarcoma