Clinical Manual for Management of the HIV-Infected Adult, 2006 Edition

Section 5: Complaint-Specific Workups

Anemia

Background

Anemia is usually characterized by a hemoglobin level of <14 g/dL in men and <12 g/dL in women. In people with HIV infection, anemia has been linked to poor quality of life and decreased survival, and correction of anemia can improve these parameters.

Anemia has many potential causes and, in HIV-infected individuals, several of these may occur concomitantly. Common causes include:

• Anemia of chronic disease
• Bone marrow suppression due to medications
• Bone marrow infiltration by infection or malignancy (eg, Mycobacterium avium complex, tuberculosis, cytomegalovirus, lymphoma, myelodysplasia)
• Nutritional deficiencies (eg, vitamin B12 or folate)
• Iron deficiency (eg, from blood loss)
• Hypogonadism

Anemia of chronic disease, due to HIV infection itself, is very common in patients with low CD4 counts (<200 cells/µL) and high HIV viral loads, as well as in those with low body mass index, and in women, African Americans, and older people (aged >50 years).

Medication-induced anemia, particularly from zidovudine (ZDV) and trimethoprim-sulfamethoxazole (TMP-SMX), is also common and may occur quickly after initiation of these medications. The risk of anemia with a ZDV-containing regimen is of particular concern in resource-limited settings where access to alternative antiretroviral (ARV) medications may be limited and the likelihood of advanced disease when starting ZDV is substantial. Careful monitoring of hemoglobin at 2-4 weeks after initiation of ZDV and regularly thereafter, and continued access to affordable alternatives, are crucial to the success of antiretroviral therapy (ART) in these settings.

S: Subjective

Patients who have gradual declines in hemoglobin may be able to compensate and remain asymptomatic even at very low hemoglobin levels. Others may complain of weakness, fatigue, shortness of breath, pallor, dizziness, syncope, nausea, anorexia, headache, palpitations, chest pain, sleep disturbance, anxiety, malaise, or confusion.

Conduct a careful history, asking about symptoms listed above, as well as the following:

• Onset and duration of symptoms
• Previous anemia (and family history of anemia)
• Blood transfusions received (if any)
• HIV disease status, including CD4 cell count, history of opportunistic infections, other illnesses
• Abnormal bleeding; dark or tarry stools
• For women, date of last menses and amount of menstrual blood loss
• Jaundice
• Other symptoms: fever, sweats, weight loss, diarrhea, lymph node enlargement
• Current and recent medications (prescribed or over-the-counter), nutritional supplements, and herbal preparations
• Use of aspirin or nonsteroidal antiinflammatory drugs
• Dietary habits
• Alcohol abuse

O: Objective

Measure vital signs, with special attention to heart rate and blood pressure. Perform orthostatic measurements. Compare current weight with previous values. Perform a careful physical examination, including the following:

• General appearance (nutritional status, appearance of health or illness)
• Skin, conjunctivae: pallor, jaundice, icterus
• Mouth: stomatitis or glossitis (vitamin B12 or folate deficiency)
• Abdomen: liver or spleen enlargement, masses
• Lymph nodes
• Extremities: edema
• Neurologic: vibratory sensations, balance and gait, deep tendon reflexes, Babinski reflexes
• Rectal: check for occult blood

A: Assessment

Remember that more than one cause of anemia may be present. A partial differential diagnosis includes:

• Chronic disease: HIV/AIDS; other comorbid conditions
• Medications
  • ZDV or ZDV-containing drugs (Combivir, Trizivir)
  • TMP-SMX (Septra, Bactrim, cotrimoxazole)
  • Other hematotoxic medications (see list, below)
• Iron deficiency
• Vitamin B12 or folate deficiency
• Malnutrition
• Alcoholism
• Malignancy
• Renal disease
• Liver disease
• Blood loss (eg, gastrointestinal)
• Hemolysis (eg, in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency who are exposed to dapsone, TMP-SMX, or other oxidants)
• Parvovirus B19
• Tuberculosis
• Mycobacterium avium complex (MAC)
• Histoplasmosis, cryptococcosis
• Malaria
• Sickle cell disease
• Thalassemia
• Hypogonadism
• Hypothyroidism
• Pregnancy
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Inflammatory bowel disease
• Hookworm infection

P: Plan

Diagnostic Evaluation

Recheck the hematocrit and hemoglobin to confirm anemia, and perform a complete blood count with differential to determine whether other cytopenias are present.

Perform laboratory work and other diagnostic studies as suggested by the history, physical examination, and differential diagnosis. Consider the following as initial tests to determine the cause of anemia:

• Mean corpuscular volume
• Peripheral blood smear
• Reticulocyte count
• Bilirubin (total and direct)
• Iron studies: ferritin, iron, transferrin, total iron-binding capacity
• Hemoccult testing for fecal blood
• Pregnancy test if indicated

See Figure 1 for a possible diagnostic approach.

Figure 1. Diagnostic Evaluation for Anemia

Key to abbreviations: AZT = zidovudine; ddC = dideoxycytidine; DIC = disseminated intravascular coagulation; HB = hemoglobin; MCV = mean cell volume; RBCs = red blood cells; TTP = thrombotic thrombocytopenic purpura

Adapted from: Volberding PA, Levine AM, Deiterich D, et al. Anemia in HIV infection: clinical impact and evidence-based management strategies (Figure 4. Simplified diagnostic approach to anemia in HIV-infected individuals). Clin Infect Dis. 2004 May 15;38(10):1454-63. Used with permission of the University of Chicago Press.

Check the testosterone level in individuals (both men and women) with anemia of uncertain cause, particularly if they have other signs or symptoms of hypogonadism. Perform further testing if indicated by the clinical presentation and results of the initial workup (eg, evaluation for parvovirus B19 or other infection, vitamin B12 deficiency, G6PD deficiency, malignancy, or gastrointestinal blood loss).

Consider bone marrow biopsy if the diagnosis is unclear, if the anemia is chronic or severe, if the initial evaluation does not determine the cause, or if the anemia is accompanied by pancytopenia. Bone marrow biopsy may also be performed to confirm a diagnosis.

Review the patient's medication list for drugs that may cause anemia. Some common medications that may cause anemia are the following:

• ZDV
• Ganciclovir, valganciclovir
• Sulfonamides
• Pyrimethamine
• Dapsone
• Ribavirin
• Interferon-alfa
• Antineoplastic agents

Refer the patient to hematology or oncology specialists as appropriate.

Treatment

The appropriate treatment depends on the cause and severity of the anemia. Refer to pertinent chapters in Section 6: Disease-Specific Treatment or primary care management guidelines as appropriate.

• Patients with severe anemia may require transfusion (unless hemolysis is suspected) with or without hospitalization for evaluation and treatment.
• Consider treating anemia of chronic disease with ART, if it is otherwise indicated, while avoiding medications associated with bone marrow toxicity. Mild anemia often resolves without intervention after the start of ART as the immune system is reconstituted.
• If drug-induced anemia is suspected, discontinue the offending medication, if possible. For example, for patients taking ZDV in whom other causes of anemia have been excluded, consider substituting another nucleoside/nucleotide analogue in place of ZDV. If it is not possible to alter therapy, consider using erythropoietin (EPO) or red blood cell transfusion to increase the hematocrit.
• EPO may be used to stimulate red blood cell production. A typical dosage of recombinant human EPO is 40,000 units weekly by subcutaneous injection. Note that EPO replacement is ineffective if the erythropoietin level is >500 international units per liter (check serum EPO levels before treatment) or if iron levels are low. For patients in whom EPO is started, monitor the hemoglobin and hematocrit regularly (eg, every week until stabilized, then every 4 weeks) and adjust the dosage as required.
• Treat hypogonadal patients with testosterone.
• Treat iron deficiency with ferrous sulfate 325 mg orally 3 times daily.
• Treat nutritional deficiencies as indicated. For folate deficiency, give folic acid 1-5 mg daily for 1-4 months; for vitamin B12 deficiency: administer cobalamin 1 g intramuscularly once daily for 7 days, then once weekly for 4 weeks, then once monthly, or 1-2 g orally once daily.

Patient Education

• Symptoms such as fatigue, weakness, and shortness of breath may be signs of anemia. Patients should notify their health care providers if they develop these or other symptoms.
• Anemia may be caused by an opportunistic infection or other illness; further evaluation may be necessary.
• Anemia often responds to treatment. For many patients, ART may be a successful treatment; encourage them to adhere to ART.
• Counsel patients to take their medications exactly as directed and to call their health care providers if they experience new or worsening symptoms.