Infection and Anemia
Infection and Anemia
By Jeffery M. Krakower
Synopsis: Anemia is common in patients with infectious diseases.
Source: Weiss G, et al. Anemia of Chronic Disease. N Engl J Med. 2005;352:1011-1023.
Anemia of Chronic Disease (ACD) is a common disorder occurring in patients with acute and chronic inflammatory conditions. ACD is associated with infectious diseases, as well as with malignancies and autoimmune disorders. The pathophysiology of ACD involves abnormalities in iron homeostasis, impaired erythropoiesis, and blunted responses to erythropoietin, brought about by mediators of inflammation such as TNF-alpha, interferon-gamma, and interleukins.
ACD is marked by disturbances in iron metabolism. Iron is diverted from the circulation to reticuloendothelial storage sites. Like iron deficiency, ACD restricts the availability of iron for erythropoiesis. In iron deficiency anemia, total body iron stores are depleted, while in ACD, total body iron stores are adequate, although not readily available for red cell production.
Since both iron deficiency anemia and ACD are marked by low serum iron and low transferrin saturation, ACD is often mistaken for iron deficiency anemia, leading to an unrewarding search for occult bleeding. A careful clinical history and thorough laboratory evaluation of iron homeostasis usually leads to the correct diagnosis. Uncomplicated iron deficiency anemia is characterized by a microcytic, hypochromic anemia, low serum iron, high iron binding capacity, low serum ferritin, and high soluble transferrin receptor assay, reflecting total body iron deficit. In contrast, uncomplicated ACD is characterized by normocytic, normochromic anemia, low serum iron, normal iron binding capacity, normal or high ferritin, and a normal soluble transferrin receptor assay.
Since ACD occurs in the setting of an acute or chronic infectious, inflammatory, or malignant disease, it is usually only 1 aspect of a multifactorial anemia. As examples, patients with ACD secondary to inflammatory bowel disease or gastrointestinal malignancies often have superimposed iron deficiency anemia. Patients with autoimmune diseases, such as SLE, may have concomitant renal disease and anemia due to relative erythropoietin deficit. Patients with endocarditis may have low grade hemolysis due to DIC or microangiopathic hemolysis from valve dysfunction. In the presence of complicating causes of anemia, the peripheral smear and iron studies become more difficult to interpret, but may offer important clues to other causes of anemia.
ACD is generally mild to moderate in severity, with hemoglobin levels of 8.0 gm% to 9.5 gm%. Examination of the peripheral blood smear is often overlooked, but may provide valuable insight into the cause of the chronic inflammatory process, as well as complicating causes of anemia. The peripheral smear, for example, may reveal evidence of an underlying hemoglobinopathy, microangiopathic hemolytic anemia, or a primary bone marrow disorder such as myelodysplasia.
The reticulocyte count is depressed in ACD and haptoglobin normal in the absence of concomitant diseases associated with hemolysis or ineffective erythropoiesis. The presence of even a modestly elevated creatinine, especially in an elderly or cachetic patient, raises the possibility of relative erythropoietin deficiency. A creatinine clearance and erythropoietin level will provide additional information, although the erythropoietin level should not be expected to be elevated with a hemoglobin of > 10.0 gm%. The erythropoietin level may also provide insight into whether the pharmacologic use of epoetin is likely to be of benefit in treating ACD.
The treatment of ACD requires that the clinician identify the underlying inflammatory disorder, since the primary treatment of ACD is elimination of the underlying infectious, malignant, or autoimmune dysfunction. Whether the anemia requires treatment, per se, depends on the severity of the anemia, as well as the general health of the patient.
Iron supplementation is not indicated unless concomitant iron deficiency has been demonstrated (eg absent bone marrow iron stores, low serum ferritin, elevated soluble transferrin receptor assay). Iron supplementation is generally ineffective in ACD. Further, excess iron levels may have detrimental effects in some patients. Iron is an essential nutrient for some microorganisms. Sequestration of iron in the reticuloendothelial system may be a defense strategy inhibiting the growth of such microorganisms.
Blood transfusions are helpful when the anemia is severe (< 8.0 gm %) or when co-existing cardiopulmonary disease exacerbates the effects of mild or moderate anemia. Transfusions carry risks including iron overload, volume overload, transmission of infectious disease, transfusion reactions, and possible immune suppression, and should not be used arbitrarily, absent clinical symptoms.
Erythropoietin may be beneficial in patients with severe anemia and relatively low erythropoietin levels. When erythropoietin is employed, the target hemoglobin level is generally 11.0 gm% to 12.0 gm%. An overly brisk rate of increase in hemoglobin level and the development of iatrogenic erythrocytosis should be avoided as both may have detrimental effects on the patient. The development of hypertension, thromboembolic events, and rarely pure red cell aplasia has been reported with the use of erythropoietin. Erythropoietin also imposes a significant financial burden, and should not be used excessively or indiscriminately. Erythropoietin supplementation should be stopped after 8 weeks if there has been no response in the absence of concomitant iron deficiency.
There remains a need for better treatments to enhance erythropoiesis in the setting of chronic inflammatory disease. Potential areas of investigation include drugs that induce endogenous erythropoietin production, hepcidin antagonists to overcome the reticuloendothelial iron retention which is characteristic of ACD, and hormones or cytokines designed to stimulate erythropoiesis despite ongoing inflammation.
Dr. Krakower is a Hematologist in Private Practice in Redwood City, CA, and is a Clinical Professor of Medicine at Stanford University.
Anemia of Chronic Disease (ACD) is a common disorder occurring in patients with acute and chronic inflammatory conditions. ACD is associated with infectious diseases, as well as with malignancies and autoimmune disorders. The pathophysiology of ACD involves abnormalities in iron homeostasis, impaired erythropoiesis, and blunted responses to erythropoietin, brought about by mediators of inflammation such as TNF-alpha, interferon-gamma, and interleukins.Subscribe Now for Access
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