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ANEMIA OF INFLAMMATION

Anemia of inflammation (AI), also known as anemia of chronic disease, refers to a

mild-to-moderate anemia that results from decreased RBC survival and production

and generally occurs over months to years.

70

It has been associated with a number of

disorders (e.g., autoimmune disorders, acute and chronic infections, chronic kidney

disease, and malignancy).

71 Because of the common occurrence of such conditions,

AI is encountered frequently and has been estimated to be the second most common

anemia after iron deficiency. Most often, AI is a normochromic, normocytic anemia,

although RBCs may be hypochromic and microcytic in less than a quarter of

patients.

72 A prominent feature of AI is the altered availability of iron which is not

reliably reflected in iron indices due to an increase of hepcidin, a hormone that

regulates iron metabolism.

73 Additionally, the EPO response may be inappropriate

for the degree of anemia.

74

The pathogenesis of AI is not well understood. It appears the production of

inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, IL-6, and IL-1

leads to either activation of macrophages that consume and destroy erythrocytes or

the suppression of erythropoiesis by inhibition of RBC precursors, such as BFUe.

75

In response to inflammation, elevated levels of IL-6 upregulate hepcidin production

through the JAK-STAT pathway, inhibiting the release of iron stores to the plasma.

This high concentration leads to hypoferremia (functional iron deficiency) and

blunted erythrocyte production.

73 Hepcidin can further alter iron hemostasis by

decreasing duodenal iron absorption.

72 A review of iron studies is important to

distinguish AI from iron deficiency anemia. In AI, serum iron, transferrin saturation,

and TIBC are low with an increased serum ferritin. Conversely, in iron deficiency

anemia, serum iron, transferrin saturation, and serum ferritin are low with an

increased TIBC. However, it is important to recognize that both forms of anemia may

be seen concurrently in patients with AI.

Management of mild-to-moderate AI usually focuses on the underlying disease

process. Anemia of inflammation is not usually progressive or life threatening,

although it generally affects a patient’s quality of life. Patients may require blood

transfusions for symptomatic anemia which are associated with risks such as

hepatitis, viral infections, iron overload, treatment-related acute lung injury, and

immunogenic reactions. Unless a concurrent deficiency of vitamin B12 or folate

exists, administration of vitamin supplements for AI is not of value. Iron

supplementation may be warranted in patients with a functional or absolute iron

deficiency anemia. Erythropoiesis-stimulating agents (ESAs) have been used

successfully to treat AI in patients with rheumatoid arthritis, acquired

immunodeficiency syndrome (AIDS), malignancy, and chronic kidney disease;

however, medication costs and increased safety risks can be significant and risk

versus benefits should be assessed when determining treatment.

72,74

Erythropoietic Therapy

Erythropoietic therapy is indicated for use in anemia associated with chronic kidney

disease, drug-induced anemia (myelosuppressive chemotherapy and zidovudine

therapy), and autologous blood transfusions for elective noncardiac, nonvascular

surgery.

76–78 Response to ESAs is dependent on both dose and the underlying cause of

anemia and may take days to weeks to be seen. Currently, there are two ESAs,

epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp), approved for use in

the United States. Darbepoetin differs from epoetin alfa by the addition of two

carbohydrate chains. The significance of the additional carbohydrate chains is an

increased sialic acid content resulting in decreased clearance and a serum half-life 3

times longer than that of epoetin alfa. These kinetic differences allow darbepoetin

alfa to be administered less frequently. Table 92-11 illustrates current therapeutic

uses of epoetin alfa and darbepoetin alfa. Lack of response to erythropoietic therapy

(ESA hyporesponsiveness) in all patient populations is most commonly associated

with iron deficiency.

Although some studies assessing the use of ESAs in the treatment of chronic kidney

disease and chemotherapy-induced anemia (CIA) have shown benefit (i.e., decreased

RBC transfusions), there is also evidence that use increases the risk for

cardiovascular events, stroke, thrombosis, shortened overall survival, and/or

increased the risk of tumor progression or recurrence in the respective patient

populations.

79,80

In 2011, the FDA mandated a Risk Evaluation and Mitigation

Strategy (REMS) program based on studies that identified safety concerns with the

use of epoetin alpha and darbepoetin alpha. Recently the FDA performed an

evaluation of the ESA REMS requirements and found that the requirements had

minimal impact on ESA utilization beyond that of CMS coverage determinations and

other FDA regulatory actions. As a result, in 2017, the FDA determined that it is no

longer necessary to require the ESA REMS requirements and the risk and benefits of

the medications can be communicated by the current product prescribing information.

Healthcare providers are encouraged to discuss the risks and benefits of using ESAs

with each patient prior to initiating use.

Table 92-11

Therapeutic Uses and Regimens for Recombinant Human Erythropoietin

(rhEPO)

a

Anemia Pathogenesis

Epoetin Alfa Darbepoetin Alfa

Dose

(units/kg) Frequency

Dose

(mcg/kg) Frequency

Zidovudine-induced 100 3 ×/week — —

Chemotherapy-induced 150 or 40,000

units (total dose)

3 ×/week or

once a week,

respectively

2.25 or 500 mcg

(total dose)

Once a week or once

every 3 weeks, respectively

Chronic kidney disease 50–100 3 ×/week On dialysis 0.45

or 0.75

Not on dialysis

0.45

Once a week or once

every 2 weeks, respectively

Once every 4 weeks

aAdult dosing.

p. 1942

p. 1943

Renal Insufficiency-Related Anemia

The cause of renal insufficiency-related anemia is complex but involves reduced

EPO production and a shortened RBC life span. Repeated transfusions are a possible

treatment but can lead to complications and should be avoided unless rapid Hgb

correction is needed. Because EPO is secreted in the kidney in response to anoxia

and is responsible for normal differentiation of RBCs from other stem cells,

erythropoietic therapy is used to treat anemia in patients with renal failure who are

undergoing hemodialysis.

79,81 A dose-dependent rise in Hct is observed in patients

with end-stage renal disease at approved doses of epoetin alfa or darbepoetin alfa

(See Table 92-11). Targeting higher concentrations of Hgb (>13 g/dL) is associated

with increased mortality and adverse effects. A FDA mandated black-box warning

for these drugs states to individualize treatment to maintain use of the lowest dose of

an ESA necessary to decrease the need for transfusion.

76–78 This target Hgb differs

from the current kidney disease guidelines.

79,82 Refer to Chapter 28, Chronic Kidney

Disease, for further information on treatment target goals as well as the appropriate

use of ESAs and IV iron in patients with renal insufficiency-related anemia.

Malignancy-Related Anemia

CASE 92-8

QUESTION 1: P.M is a 62-year-old woman diagnosed with Stage IV ovarian cancer. She is being seen for

her fourth cycle of chemotherapy with carboplatin and paclitaxel. She reports shortness of breath and fatigue

when she walks up stairs but otherwise has a good performance status. Her CBC indicates the following:

Hgb, 9.7 g/dL

Hct, 29%

MCV, 90 mcm

3

Reticulocytes, 100 × 10

3

/mcL

The peripheral smear shows normochromic and normocytic RBCs and iron studies are within normal limits.

What is the most likely cause of P.M.’s anemia? What is the appropriate treatment?

P.M. appears to have malignancy-related anemia, which can be characterized as

AI or CIA. Anemia is common in cancer occurring in up to 30% to 90% of patients.

83

The etiology of anemia in cancer patients is frequently complex and a conglomeration

of various attributing factors such as comorbidities, malignancy, blood loss,

nutritional deficiencies, and treatment with radiation and/or chemotherapy.

84

Chemotherapy-induced anemia is the result of hematopoietic impairment affecting

RBC production and nephrotoxic effects of chemotherapy agents, such a platinumcontaining agents, decreasing erythropoietin production.

80

It is generally normocytic

and normochromic and develops over the course of treatment.

85 As with P.M., the

CIA is often classified as mild to moderate and patients present as asymptomatic or

mildly symptomatic (weakness, decreased exercise tolerance).

86 Factors that can

influence the incidence of malignancy-related anemia in patients with cancer are the

type of malignancy and the stage and duration of disease; the type, schedule, and

intensity of treatment; and history of prior myelosuppressive chemotherapy or

radiation. Cancer patients receiving chemotherapy should be routinely screened for

CIA with a CBC. As per the NCCN Clinical Practice Guidelines in Oncology

(NCCN Guidelines), evaluation for CIA should begin at an Hgb ≤11 g/dL. Additional

tests including a peripheral blood smear and reticulocyte count as well as other

potential causes of anemia should be performed.

The recommended treatment for CIA is comprised of transfusion or use of ESAs

with or without iron supplementation.

80 Therapy should be directed to the underlying

disease, if possible. When considering treatment options, transfusion with packed red

blood cells (PRBC) should be used when rapid correction of Hgb is warranted with

an expected 1 g/dL increase in Hgb and 3% increase in Hct with a single unit of

PRBC. The use of transfusion for chronic management is associated with known

risks, notably an increased risk of thromboembolic events in patients with cancer.

87

Conflicting data exist regarding the effect of transfusion on mortality.

80 ESAs with or

without iron supplementation should be considered for long-term management of

anemia in a patient with cancer because it has been shown to reduce transfusion

requirements. Large, randomized, multicenter trials have failed to show a clinical

benefit to using ESAs in anemia that is not chemotherapy-induced. The reported

increased risk of mortality and tumor progression in clinical trials of anemic patients

with head and neck, breast, nonsmall cell lung, lymphoid, and cervical cancers

receiving ESAs resulted in a black-box warning being added to all ESA product

information to advise about these and other increases in serious adverse events.

88

ESAs are recommended for anemic patients with cancer who are receiving

myelosuppressive chemotherapy and the intent of treatment is not curative, with the

possible exception of small cell lung cancer as there are no clinical trials reporting a

deleterious impact on survival. As recommended by the FDA, treatment with an ESA

should not be initiated until the Hgb is less than 10 g/dL and there is an additional 2

months of chemotherapy planned. The lowest dose needed to avoid RBC transfusion

should be given, and use should be discontinued at the end of chemotherapy

treatment.

76–78 Although response rates to ESAs have been reported upwards of 70%

to 80% in clinical trials, not all patients will respond to treatment.

89 The most

common cause of nonresponse to erythropoietic therapy is absolute or functional iron

deficiency. Iron studies should be evaluated before and during therapy with

supplementation given if needed. Oral or intravenous iron may be used for

supplementation but data from clinical trials show intravenous iron is superior when

given with an ESA.

80

In P.M.’s case, the clinician may choose from a number of anemia management

options. For example, the current course of chemotherapy can be delayed to allow for

hematologic recovery and resolution of anemia symptoms. Alternatively, an RBC

transfusion can be given to relieve her symptoms and allow her to better tolerate

chemotherapy. Erythropoietic therapy with epoetin alfa or darbepoetin alfa also

should be considered because the patient has metastatic disease (not curative) and

will continue on chemotherapy until disease progression. Treatment with epoetin alfa

or darbepoetin alfa increases Hgb and decreases the need for blood transfusions. If

treatment with epoetin alfa is desired for P.M., therapy can be administered at an

initial dose of 150 units/kg subcutaneously 3 times a week or 40,000 units once a

weekly.

77,78 Alternative dosing regimens, 80,000 units every 2 weeks or 120,000

units every 3 weeks, have proved to be safe and effective in terms of hematopoietic

and transfusion effects.

80,90 Darbepoetin alfa is also a treatment option for P.M. Initial

dosing of darbepoetin alfa is 2.25 mcg/kg subcutaneously once a week or 500 mcg

every 3 weeks.

76,91 Alternative dosing regimens of darbepoetin alfa 100 mcg once

weekly, 200 mcg every 2 weeks and 300 mcg every 3 weeks have reported similar

beneficial effects seen with epoetin alfa.

93–94 Response of ESAs is monitored by

measuring Hgb weekly

p. 1943

p. 1944

until stabilization. During this time, the dose should be titrated to the lowest dose

needed to avoid transfusion. A minimum of 2 weeks is required before an increase in

RBCs is seen. A reduction in dose (25% for epoetin alfa and 40% for darbepoetin

alfa) is required if there is a greater than 1 g/dL rise in the Hgb in any 2 week period

or the Hgb reaches a level to avoid transfusion. If no response (less than 1 g/dL rise

in Hgb and Hgb remains below 10 g/dL) is seen in 4 weeks with epoetin alfa or 6

weeks with darbepoetin alfa, a dose increase should be considered. Common dose

escalation schedules for epoetin alfa include escalating to 300 units/kg 3 times a

week if initially treated with 150 units/kg 3 times a week or 60,000 units once a

week if initially on 40,000 units once a week. Dose escalation for darbepoetin would

consist of an increase to 4.5 mcg/kg once weekly if prior treatment was 2.25 mcg/kg

weekly. The need for iron supplementation should also be considered at this time.

Response should again be assessed at week 8 or 9 and appropriate dose reductions

made based on Hgb level or transfusion avoidance. If no Hgb response is noted after

8 or 9 weeks of treatment or transfusions are still required, the drug should be

discontinued.

76–78

Human Immunodeficiency Virus (HIV)-Related Anemia

Anemia is a common finding in patients with HIV and correlates with the severity of

disease as well as clinical outcomes.

95

In this patient population, anemia that has

been identified is an independent prognostic factor for increased morbidity and

mortality.

96

It has also been shown to be a marker of treatment failure in patients who

do not achieve viral suppression and thus should be monitored as part of treatment.

97

Several factors may lead to the development of anemia in HIV patients including

infections, malignancies, the presence of genetic disorders of hemoglobin, nutritional

deficiencies, and the use of combination antiretroviral therapy (cART). Examples of

infections includes bacteria (Mycobacterium avium complex disease), fungus

(Histoplasmosis), and viruses (CMV, herpes simplex viruses type 1 and 2, and HPV

B19). The use of myelosuppressive cART drugs such as zidovudine, zalcitabine,

didanosine, lamivudine, and other medications often used to treat AIDS-associated

illnesses (e.g., bone marrow suppressive chemotherapy, ganciclovir, trimethoprim–

sulfamethoxazole, dapsone) also contributes. Additionally conditions like

malignancies, Kaposi’s sarcoma, and lymphoma, all of which impair normal bone

marrow function, predispose these patients to anemia.

98 Vitamin B12 deficiency is a

contributing cause to anemia in up to a third of patients

97 and is correlated with

progression to AIDS.

99 Vitamin B12 malabsorption can result from HIV-infected

mononuclear cells within the ileum and altered gastric mucosal functioning caused by

infection.

100 Alterations in the utilization of vitamin B12 and folate

101 can place a

patient at risk for hematologic toxicity from drugs such as zidovudine and

trimethoprim. More recently, evidence suggests the actual virus may play a role in the

pathophysiology resulting in decreased erythropoiesis and erythropoietic response.

95

Common features of HIV-related anemia are comprised of a decreased reticulocyte

count, morphologically normochromic and normocytic RBCs, adequate iron stores,

and impaired response to erythropoietin.

95

Treatment for HIV-related anemia consists of erythropoietic therapy or removal of

the offending drug, if possible. Erythropoietic therapy has demonstrated increases in

Hgb and quality of life in HIV-infected adult patients, regardless of drug therapy,

CD4

+ count, or viral load.

100 While no longer first-line treatment for HIV in the

United States, zidovudine is still used in pregnant women and children as well as in

developing countries. Its use is associated with the development of cytopenias,

primarily anemia, that occur within 3 to 6 months of beginning treatment.

102 Clinical

studies show patients taking zidovudine who have baseline erythropoietin levels less

than 500 units/L experience a significant reduction in transfusion requirements.

103

Epoetin alfa therapy may be initiated in patients with zidovudine-induced anemia at

100 units/kg 3 times weekly. RBC indices should be closely monitored. If the Hgb

exceeds 12 g/dL, then the dose should be held until it declines to less than 11 g/dL.

At that time a dose reduction of 25% or to the lowest dose necessary to prevent RBC

transfusion is recommended. If a patient has no response after 8 weeks of therapy, the

dose should be increased by 50 to 100 units/kg 3 times weekly at 4- to 8-week

intervals or increased to 300 units/kg 3 times weekly. If no response is seen at a dose

of 300 units/kg for 8 weeks, it is unlikely that the patient will benefit from further

therapy and the drug should be discontinued.

76–78 Alternative once-weekly dosing

with epoetin alfa has been evaluated at starting doses of 40,000 units.

104 The use of

darbepoetin alfa has been assessed in HIV patients receiving hemodialysis and is as

safe and effective as epoetin alfa for treating anemia.

105

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

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