Complete Blood Count with Red Blood Cell Indices, White Blood Cell Differential, and Platelet Count

Who Should Be Tested

Newly arrived refugees of all ages and ethnicities.

Potential Disorders Detected

A. Anemia

Anemia is a common finding in refugees of all ages and ethnicities. The prevalence of anemia in selected groups of newly arrived populations has ranged from 19% among African refugees resettling in Australia to 37% among Southeast Asian refugees resettling in the United States.^{2  3}  Anemia was identified in 12% of 1,247 refugee children

in Massachusetts, with a rate of 29% among children under 2 years.⁴  In addition, a study in Maine found 20% of 127 refugee children were anemic at the time of their new-arrival medical evalution.⁵

Anemia may result from a wide range of disease processes. Common causes of anemia in refugee populations include iron deficiency, inherited hematologic abnormalities (e.g., thalassemias, hemoglobinopathies, enzyme defects), and infectious diseases (e.g., malaria, intestinal parasitosis). The ultimate cause is often multifactorial;⁶  therefore, the clinician needs to consider multiple conditions whenever anemia is detected. The complete evaluation of anemia in refugees is beyond this scope of this document, but common causes and initial testing are discussed below and summarized in Table 2.

Iron-Deficiency Anemia (IDA)

IDA, probably the most common cause of anemia in immigrant populations, is usually manifested as a microcytic anemia (Table 2). The groups most commonly affected are children and women;⁷  however, refugees of both sexes and all age groups are at risk. Although IDA is frequently multifactorial, it is primarily caused by deficient dietary iron. Chronic blood loss, which frequently adds to iron deficiency, is commonly caused by infection with intestinal parasites, particularly hookworm. Helicobacter pylori infections may lead to gastrointestinal blood loss through ulcer formation. If iron deficiency has not been longstanding or severe, frank anemia may not result, but changes in red blood cell morphology, including microcytosis (low mean corpuscular volume) and increased red cell distribution width (RDW), may be noted. In a convenience sample of newly arrived western, central, and eastern African refugees to Australia, 20% had ferritin levels that indicated iron deficiency.²  Studies in the United States have also shown a high prevalence of iron deficiency in Southeast Asian refugees.⁸

Iron deficiency likely increases intestinal absorption of lead.⁹  To address the high prevalence of iron deficiency in refugee children and decrease their likelihood of developing elevated lead levels after arrival to the United States, CDC recommends that all children aged 6 months to 16 years have a lead level test and all children aged 6 to 59 months receive pediatric multivitamins after arrival (see Lead Section for more details).

Inherited Anemias

Inherited hematologic disorders are common among many refugee populations and should be considered in any refugee who has anemia detected on screening, even if other potential causes exist (e.g., iron deficiency, particularly if not corrected with therapy). These disorders include thalassemias, hemoglobinopathies, enzyme defects, and cell membrane defects. These conditions are most common in malaria-endemic regions, since they may provide some defense against this infection. Most of these conditions are autosomal recessive (except for glucose-6-phosphate dehydrogenase deficiency, which is an X-linked disorder). Therefore, it is important to both identify symptomatic refugees who are homozygous for an abnormal gene and to detect heterozygous carriers, since their offspring may be affected by the disease (Table 2).

Thalassemias are a group of disorders characterized by a decrease in either the alpha or beta globin chain production in red blood cells (RBCs). Globally, most people with thalassemia are born in or are descended from populations in eastern Asia, the Philippines, Indonesia, India, Pakistan and the Middle East.^9 10   A large increase in the prevalence of all forms of thalassemia has been reported in North America, mostly as a result of immigration from Asian and Middle-Eastern groups in recent decades. ¹⁰   In California, the rate of hemoglobin H disease (or α-thalassemia) in newborns is high for several Asian immigrant populations: 1/2,500 in Chinese and Vietnamese, 1/1,400 in Filipino, 1/800 in Cambodian, and 1/160 in Laotian newborns. ¹⁰

Four conditions make up the α-thalassemias, defined by the number of inherited deletions of the four alpha globin genes.¹⁰   If only one deleted gene is inherited, the person is a silent carrier. Alpha-thalassemia trait occurs when two deleted genes are inherited (either [a_/a_] or [aa/__). Affected people are asymptomatic but usually have a mild microcytic anemia. This condition is important to identify, as the red cell indices resemble IDA; however, administration of iron in alpha-thalassemia trait may be harmful to the patient. When three deleted alpha globin genes are inherited, the result is α-thalassemia (hemoglobin H disease). Affected people have microcytic hypochromic anemia at birth and may have aplastic or hemolytic crises throughout life as a result of viral infections. Hemoglobin H disease may present with complications of gallstone formation or physical exam findings of splenomegaly or growth failure.⁸   Roughly half of people with hemoglobin H disease have inherited two deleted alpha globin genes, in combination with a nondeletional mutation called the “constant spring mutation.” These people may have a more severe clinical course than those with the classic three-deletion hemoglobin H disease.⁸   If a fetus inherits four deleted alpha globin genes, hemoglobin Bart’s disease results. Typically, these fetuses do not survive.⁸

People who have inherited one deleted beta globin gene have β-thalassemia minor (trait). These people have mild microcytic anemia but have no symptoms related to the condition. People who have inherited two deleted beta globin genes have β-thalassemia major. Typically symptoms manifest at 8 to 10 months of life, after fetal hemoglobin production has stopped. These patients have severe anemia and fatigue. They may have frontal cranial bossing, other bony changes, and liver and spleen enlargement as a result of extramedullary hematopoesis. Affected people may be jaundiced and are at increased risk of gallstone formation. This condition typically requires frequent blood transfusions and iron chelation.⁸

The hemoglobinopathies are conditions characterized by production of abnormal globin chains. Perhaps the most widely known of these conditions is sickle cell disease, due to replacement of glutamic acid by a valine at the sixth amino acid position of the beta chain. Globally, 80% of people affected by sickle cell disease live in or have origins in central Africa. The condition also affects people from Central and South America, the Arabian Peninsula, Middle East, India, and eastern Mediterranean.¹¹

Hemoglobin E trait, caused by substitution of a lysine by a glutamic acid at position 26 of the beta chain, is another hemoglobinopathy that is frequently present in certain refugee groups, particularly from Southeast Asia. Both heterozygotes and homozygotes are asymptomatic but have hypochromic microcytosis and mild anemia.¹²   However, in people who are carriers of both the hemoglobin E gene and the beta-thalassemia gene deletion, severe anemia may result. The prevalence of hemoglobin E is very high in areas of Southeast Asia – nearly 60% in regions of Thailand, Laos, and Cambodia. ¹⁰   In California, 25% of Cambodian newborns and just over 10% of Thai and Laotian newborns are hemoglobin E carriers. ¹⁰   Hemoglobin E is also seen in many people from Indonesia, Bangladesh, northeast India, Sri Lanka, and parts of the Middle East.^{8  12}   As with the thalassemias, hemoglobin E red cell indices are similar to IDA; however, unless the patient is also iron deficient, administration of iron will not improve the condition and may be harmful.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme present in red blood cells. G6PD deficiency is the most common inherited enzyme deficiency, affecting over 400 million people globally. In certain circumstances it may cause acute hemolytic anemia. The geographic distribution of this condition matches that of the thalassemias listed above, but the condition is particularly common in Southeast Asia.¹¹   The enzymatic function of G6PD helps recycle glutathione inside RBCs. Glutathione is important for preventing oxidative damage to RBCs, which can occur when hemoglobin interacts with oxidizing agents. RBCs become rigid, resulting in their hemolytic destruction in the spleen and other reticuloendothelial organs. Intravascular hemolysis may also occur. Since the gene that codes for G6PD is located on the X chromosome, men are typically more severely affected than women. Most people with G6PD deficiency are asymptomatic until exposed to oxidizing medications. Examples of particular concern for refugee populations include sulfas, primaquine for malaria, and dapsone, which is commonly used for leprosy and as a prophylactic agent in HIV-infected people. Laboratory findings during an acute hemolytic event include normocytic anemia, increased reticulocyte count, normal liver enzymes, and an elevated indirect bilirubin. A urinalysis may be heme positive without RBCs on microscopic examination.⁸

To prevent an acute hemolytic episode, any refugee from a high-risk area should be tested for G6PD activity before oxidizing medications are prescribed. In addition, the new-arrival medical exam should include historical questions to identify past episodes of hemolysis, including prolonged or unusually severe neonatal jaundice, recurrent episodes of anemia, hemoglobinuria, jaundice, or gallstones. If the patient comes from a high-prevalence area, a positive history for any of these conditions warrants testing for G6PD deficiency prior to use of any oxidizing agents.⁸

B. Eosinophilia

Eosinophilia may be defined as an eosinophil percentage exceeding 5% or an absolute eosinophil count (AEC) exceeding 400 eosinophils/mm³ (some authors use AEC of >500 mm³). The AEC is generally a better reference, as frequently a patient will have a normal eosinophil percentage when the AEC is elevated, indicating an infection or other condition. If laboratory reports do not include the AEC, it can calculated by multiplying the total white blood count by the eosinophil percentages.

Eosinophilia in a newly arrived refugee most likely indicates the presence of a parasitic infection (see Presumptive Treatment and Medical Screening for Parasites in Newly Arriving Refugees), although other etiologies such as allergies, medication reactions, and atopy, may account for the finding (Table 2).

C. Thrombocytopenia

A variety of conditions may cause thrombocytopenia, including many infectious diseases, although a discussion of the complete differential diagnosis and evaluation of thrombocytopenia is beyond this text. However, some conditions rare in the general U.S. population may be common in certain groups of refugees and are noted here. These include any tropical infection that may cause hypersplenism (especially schistosomiasis, visceral leishmaniasis and malaria, or more rarely, brucellosis). In addition, certain infections that may not elicit clinical symptoms during the examination may cause thrombocytopenia through other mechanisms, such as HIV infection (up to 40% of infected people will have low platelet counts) or acute infection with malaria in a semi-immune person.⁸

D. Other Conditions

A CBC with differential may reveal clues to a wide range of other, less common disorders such as malignancy (e.g., leukemia), vitamin deficiencies indicated by megaloblastic anemia (e.g., B12, folate), anemia of chronic disease, and endocrinopathies (e.g. thyroid disease) (Table 2).

Initial evaluation of anemia and follow-up testing:

If anemia is present, the cause should be sought (Table 2). The large number of differential diagnoses and often multifactorial causes mean that an anemia cannot be assumed to be due to common iron deficiency. ⁶  All patients with a microcytotic anemia should have iron studies checked. If iron deficiency is not present or is unresponsive to therapy, hemoglobin electrophoresis should be performed to identify thalassemias and hemoglobinopathies. Alpha-thalassemia trait cannot be diagnosed by hemoglobin electrophoresis beyond the newborn age; it can only be inferred as the cause of iron-nonresponsive microcytic anemia in a person with a normal hemoglobin electrophoresis and no other identifiable source of microcytic anemia.⁸

Additional tests to consider include blood lead levels for any person with anemia or microcytosis (although blood lead testing is routinely recommended in children 6 months to 16 years; see Lead Section). In addition, given the very high infection rates, H. pylori, which results in peptic ulcer disease, should be considered in people with microcytic anemias, especially among those who do not respond well to iron replacement or who have abdominal complaints. ¹³

If eosinophilia is detected, the necessary follow-up testing depends on the type of pre-departure parasite treatment the refugee received (See Presumptive Treatment and Medical Screening for Parasites in Newly Arriving Refugees).

The evaluation of thrombocytopenia may be extensive. Any refugee from a malaria-endemic country should be tested for malaria as an initial step. Initial or repeat testing for HIV should be considered. When thrombocytopenia and splenomegaly are present, the patient should be referred to a specialist for evaluation for infections (e.g., schistosomiasis, leishmaniasis, and malaria), as well as other possible causes, such as malignancy.

After a careful history and physical examination, most clinicians will begin evaluation with a peripheral blood smear for morphology. An initial differential diagnosis may be generated by using the red blood cell indices.

Table 2. Common causes of anemia in refugees and recommended initial testing

• ^c Commonly multifactorial in refugees. If high, RDW may have mixed microcytic, normocytic or macrocytic causes.
• ^d Many causes, including nutritional, direct blood loss (e.g., menses, ulcer disease, carcinoma, hookworm infection), chronic disease.
• ^e If no iron deficiency or if iron-deficiency anemia is not completely corrected with iron therapy.
• ^f Particularly important in children. Not a cause of anemia, but rather a consequence of iron deficiency.

Note: G6PD does not cause anemia unless oxidative stress induces hemolytic anemia. It should be checked, particularly in Southeast Asian populations, before medications are prescribed with oxidizing potential (e.g., sulfa agents, primaquine).