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Community and International Nutrition
Research Communication

Use of Combined Measures from Capillary Blood to Assess Iron Deficiency in Rural Kenyan Children¹

Departments of Anthropology and International Health, University of Washington, Seattle, WA 98195 and ^* Department of Anthropology, Northwestern University, Evanston, IL 60208

²To whom correspondence should be addressed. E-mail: bsd{at}u.washington.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Community-based surveys of iron deficiency (ID) require simple, accurate methods that can be used in remote areas. The objective of this study was to assess iron status in rural Kenya using "field-friendly" methods for capillary blood, including an improved dried blood spot assay for transferrin receptor (TfR). A single finger stick was used to obtain capillary blood from 275 school-age children. Whole blood was applied directly to filter paper, dried, and later analyzed for TfR, as well as C-reactive protein (CRP), an acute-phase protein that serves as a general marker of inflammation. Capillary blood was also used to measure hemoglobin (Hb) concentration and the ratio of zinc protoporphyrin to heme (ZPP:H). The Hb concentration alone provides the lowest estimate of the prevalence of ID (8.0%). Because ZPP:H is reported to be elevated in the presence of inflammation, we constructed a preliminary diagnostic model based on elevated ZPP:H and normal CRP level, estimating the prevalence of ID at 25.9%. When TfR is added to a multiple criteria model (elevated ZPP:H in the absence of elevated CRP and/or elevated TfR level) the prevalence of ID is estimated to be 31.2%. This study demonstrates the diagnostic utility of combining TfR with other indexes of iron status, enabling the detection of ID in both the presence and absence of infection. Furthermore, this study is the first field application of TfR blood-spot methods, and it demonstrates their feasibility in remote field settings.

KEY WORDS: • iron deficiency • serum transferrin receptor • zinc protoporphyrin to heme ratio • C-reactive protein • capillary blood

Iron deficiency anemia is the most common micronutrient deficiency worldwide, with the highest prevalence found in developing countries (1). Recent work has focused on the inadequacy of methods for obtaining global estimates of iron deficiency (ID),³ which are calculated indirectly from indexes of anemia—hemoglobin (Hb) concentration or hematocrit—that are neither sensitive nor specific to ID (2). These measures fail to detect mild to moderate forms of ID, which even in the absence of anemia may be associated with functional impairments (3). Moreover, ID is often assumed to be the primary cause of anemia, although there are other well-known potential causes of anemia, including chronic infection, blood loss or hemolysis from parasitic infection, hemoglobinopathies such as sickle cell or thalassemia, and other nutrient disorders such as folate and vitamin A deficiencies (4–6).

The accuracy of ID assessment is improved by combining hemoglobin or hematocrit with independent measures of iron status, such as serum ferritin (SF) or erythrocyte protoporphyrin (7,8). However, multiple-criteria models based on combined measures of iron status have proven problematic in field-based studies, because the presence of inflammation alters many indexes, confounding the detection of ID during infection. Serum transferrin receptor (sTfR) is a sensitive index of iron deficiency anemia (IDA) as well as preanemic iron deficiency [iron-deficient erythropoiesis (IDE)]. In addition, recent studies demonstrate that sTfR accurately reflects iron status in the presence of inflammation (9–13). Therefore a growing body of evidence suggests that sTfR enables the identification of ID in the presence of infection, a situation that commonly occurs in developing countries with high levels of disease stress.

A second limitation to assessing iron status through combined independent measures of iron is that they often require volumes of blood necessitating venous blood draws, which can be difficult to obtain and store under field survey conditions. Venipuncture is relatively invasive, particularly in infants and children, and requires access to facilities where samples can be promptly processed, quick-frozen, or immediately assayed. In response to these challenges, a number of investigators have explored methods for determining iron status from capillary blood samples.

Capillary blood collected and sealed in microhematocrit tubes has been used to assay serum ferritin (14) and erythrocyte propoporphyrin by two methods: direct assay by hematofluorometer (14) and the zinc protoporphyrin:heme (ZPP:H) ratio of Labbe et al. (15). Capillary blood samples have also been collected on filter paper, and dried and stored for later analysis. Assays modified for dried blood spots (DBS) have been developed for a growing number of analytes, including retinol (16), C-reactive protein (CRP; 17,18), and Epstein-Barr virus antibodies (18), as well as two indexes of iron status: SF (19) and sTfR (8,20). The advantages of DBS methods include ease of storage and transport, improved safety in handling, and stability at ambient temperatures for 2 wk, thus eliminating the need to maintain a cold chain (8,19,20). Yet barriers to the widespread adoption of DBS methods for sTfR and SF include the requirement of extensive field processing, such as centrifugation to obtain serum (for SF) and pipetting premeasured volumes of blood or serum onto filter paper (8,19). Recently, DBS assays for TFR have been modified to overcome these constraints (20). However, this method has not previously been field tested.

The objectives of this study were: 1) to conduct a field trial of a recently modified whole-blood spot assay for TfR; 2) to use capillary blood samples to determine CRP, ZPP:H, and Hb levels; and 3) to evaluate the diagnostic utility of multiple-criteria models based on combined measures of inflammation and iron status in a population with high levels of disease stress.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Study area and study population. The study was conducted in July 1999 in Marsabit District, Kenya’s largest but least populated district, located in the remote northern aridland region. The timing of this study coincided with a national nutrition survey in Kenya designed to determine the prevalence of anemia and ID (21). The national survey covered 12 districts, but excluded Marsabit District due to its remoteness and lack of laboratory facilities. This study evaluated the prevalence of ID in Marsabit school-age children in one highland community, Karare, and one lowland desert community, Korr. Following the construction of community maps and a complete census of 5- to 10-y-olds, 300 children were selected in a 30-strata sampling design. Children’s ages were determined by reports from parents or primary caretakers using a local event history calendar, and by the dates of birth recorded on clinic cards. Discrepancies were resolved by relative ranking with other children in the community. The study protocol was reviewed and approved by the Human Subjects Division at the University of Washington and the Ethics Committee at Kenyatta Hospital in Nairobi.

    Assessment of iron status and health. Sterile disposable microlancets were used to collect free-flowing capillary blood to assess iron status and presence of inflammation. Iron status and anemia were assessed by Hb, ZPP:H, and transferrin receptor (TfR). C-reactive protein—an acute-phase protein that increases dramatically in association with nonspecific inflammatory responses—was used to identify individuals with infection or inflammation that could confound measures of iron status (9,10,22).

Hemoglobin concentration in capillary blood was determined in the field using the portable HemoCue B-Hemoglobin system (HemoCue). The instrument was calibrated daily, and anemic individuals were identified by subnormal hemoglobin levels, using World Health Organization cutoff values adjusted for ethnicity, as well as for altitude in the highland community of Karare (23).

Capillary blood was also collected in heparinized capillary tubes for the assessment of ZPP:H. The use of capillary blood for determining ZPP:H is well established (14,24–26). Tubes were sealed, stored for a maximum of 14 d, and transported to the United States. Samples were analyzed using the ProtoFluor-Z Hematofluorometer (Helena Laboratories). A cutoff value of 80 µmol/mol was used to indicate elevated ZPP:H level (27).

To determine TfR and CRP, 2 drops of whole capillary blood was collected on standardized filter paper (Schleicher & Schull No. 903). Samples were allowed to dry overnight, sealed in plastic bags with desiccant, and stored under refrigeration for 14 d until transport to the United States. Samples were stored at the Laboratory for Human Biology Research at Northwestern University at -20°C until analysis. Earlier research demonstrated that TfR in DBS is stable for 28 d (8), and CRP is stable for 8 wk and 1 y when stored at 4 and -20°C, respectively (28). C-reactive protein level was assayed using an ELISA protocol developed for whole-blood spots (28).

Transferrin receptor level was assayed using a commercially available ELISA kit (TF-94; Ramco Laboratory), modified for whole-blood spots (20). The DBS method for assessing TfR employed here is an improvement of an earlier method developed by Cook and colleagues (8) in that it does not require premeasurement of the blood applied to the filter paper, and it can be performed with a commercially available kit (20). Current plasma and serum protocols suggest a cutoff value of 8.5 mg/L for distinguishing iron sufficiency from ID (10,29). Based on the plasma–blood spot correlation conducted by McDade and Shell-Duncan (20), this corresponds to a blood-spot TfR concentration of 6.7 mg/L.

Thick and thin smears were prepared on glass slides for assessment for malaria parasites. The slides were fixed and stained with Giemsa stain and screened for malaria parasites at the Laboratory of Medicine at the University of Nairobi. Only the presence or absence of malaria parasites was reported.

Urine samples were collected on the day of nutritional assessment to screen for microhematuria, which often arises from schistosomiasis (30,31). Hematuria was tested using Hemastix reagent strips (Bayer), which generally detect 0.15–0.62 mg/L of free hemoglobin.

    Statistical analysis. Hemoglobin and CRP levels were normally distributed and therefore presented as means ± SD. The TfR and ZPP:H levels had skewed distributions, and therefore the geometric mean ± SD was computed. Pearson’s correlation coefficients were used to examine the relationships among iron status indexes, as well as CRP. Next, we calculated the prevalence of anemia based on subnormal hemoglobin level, as well as the prevalence of ID (both IDE and IDA) based on single and combined indexes of iron status. Because inflammation may alter ZPP:H level (32), it may not be a reliable indicator of iron status in the presence of infection. Therefore, in determining ID using ZPP:H as the only marker of iron status, children with elevated ZPP:H level and CRP concentration > 1.5 mg/L were removed from the analysis. In a final multiple-criteria model, IDE was identified by normal hemoglobin concentration, elevated ZPP:H level in the presence of normal CRP concentration, and/or elevated TfR level. Iron deficiency anemia was defined by subnormal hemoglobin level, elevated ZPP:H level in the presence of normal CRP concentration, and/or elevated TfR level. The proportion of ID identified in each model was compared by ² analysis. Values of P < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Complete hematological data were available for 275 individuals who participated in the field study. The transport and storage of blood-spot samples was straightforward, although 18 samples could not be analyzed for TfR due to insufficient quantity of remaining dried blood. Losses of 5 samples stored in capillary tubes occurred due to breakage or loss of seals, resulting in desiccated blood samples that were unsuitable for analysis. Clotting of blood samples precluded analysis of 2 additional samples.

The two markers of ID, ZPP:H and TfR, were elevated in 32 and 18.5% of the subjects, respectively (Table 1). The prevalence of inflammation, indicated by elevated CRP concentration, was 15.6%. Pearson’s correlation coefficients were used to examine the relations among iron status indexes and the relation between iron status and inflammation. There was a strong positive correlation between blood-spot TfR and ZPP:H ratio (Table 2), and a negative correlation between TfR and hemoglobin. Hemoglobin was also negatively correlated with CRP, suggesting that anemia might partially be caused by inflammation. Blood-spot TfR and ZPP:H, by contrast, were not correlated with CRP, consistent with previous reports that ZPP:H is less altered by infection than SF (10) and that TfR level is not affected by inflammation or infection (10,33,34).

The prevalence of anemia and ID was estimated using different combinations of hematological indexes (Fig. 1). Anemia, determined by hemoglobin concentration or hematocrit, is the measure most commonly used to screen for ID (7), and among Kenyan children, hemoglobin concentration provides the lowest estimate of the prevalence of ID (8.0%). Rettmer et al. (7) recommend the use of ZPP:H in single-measure screening for ID, because it is more sensitive and accurate than hemoglobin, detecting both IDA and preanemic IDE. However, because infection may alter ZPP:H (32), it is not a reliable indicator of ID in the presence of infection. Therefore, children with elevated ZPP:H level and CRP concentration were removed from the analysis. By these criteria, the prevalence of ID was estimated to be 25.9%. The TfR cutoff value of 6.7 mg/L detects a significantly lower prevalence of ID (18.5%) than the ZPP:H model (P < 0.01), but a greater prevalence than hemoglobin alone. However, because a growing body of research finds that infection does not affect TfR (10,29,33), ID can also be detected in children with elevated CRP concentration. Hence, we created a multiple-criteria model in which IDE was identified by normal hemoglobin concentration, elevated ZPP:H level in the presence of normal CRP concentration, and/or elevated TfR level. Iron deficiency anemia was identified by subnormal hemoglobin concentration; elevated ZPP:H level in the presence of normal CRP concentration, and/or elevated TfR level. This model identified iron deficiency in 31.2% of the Kenyan children (IDE and IDA combined), which does not differ from the ZPP:H model. However, combining TfR with other indexes of iron status enabled the identification of ID in children with elevated CRP levels—children that would otherwise be missed by the ZPP:H model. Of the 43 individuals with elevated CRP concentrations, 11 (25.6%) had TfR concentrations above the cutoff. Consequently, the combined measures of iron status and inflammation have the advantages of not only improving accuracy (37), but also of enabling the assessment of iron status in subjects with concurrent infection.

View larger version (30K): [in this window] [in a new window]   FIGURE 1 Estimates of iron deficiency, manifesting both as iron deficiency anemia (IDA) and iron-deficient erythropoiesis (IDE), in Kenyan 5- to 10-y-old children according to various hematological indexes (n = 275).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The main disadvantage of the methods used here is that the assay for TfR is expensive ($10 to $12 per sample for reagents and supplies), although the cost is likely to come down in the future as the assay becomes more widely used. In addition, the convenience and cost savings associated with the whole-blood methods using capillary tubes or spots dried on filter paper are diminished if plasma is required for other analytes. For example, current assays for ferritin require plasma or serum (38), because erythrocytes interfere with the assay by releasing ferritin upon lysis (8). Because SF corresponds to body iron stores, and sTfR level reflects tissue iron status, some have argued that these measures together provide a comprehensive assessment of iron status over its entire range (39,40).

However, SF is an acute-phase protein, and its concentration may increase with infection or inflammation above subnormal levels even in the presence of iron store depletion, thereby limiting the diagnostic utility of SF in determining iron status in populations with high levels of endemic disease stress (10,41,42). Statistical corrections, such as increasing the SF cutoff value to account for infection-related elevations, have not successfully corrected for underreporting of ID based on SF or the elevated ratio of sTfR to SF (10). Consequently, the most promising application of blood-spot TfR may be as a an index of iron status used in combination with hemoglobin concentration or hematocrit, along with other iron status indexes, such as ZPP:H, that are less affected by infection.

To date, sTfR has been used to detect ID in only one large-scale study in a developing country (10), and that study used venous blood samples. Our study among rural Kenyan children is the first field application of TfR blood-spot methods, and it demonstrates that blood-spot samples are easy to obtain, store, and transport in a remote field setting with a harsh climate and no laboratory facilities. Also, blood-spot TfR values are positively correlated with two other measures, hemoglobin concentration and ZPP:H level. Moreover, like ZPP:H, TfR was not correlated with CRP, and thus appears to be a reliable indicator of iron status in the presence of infection. This study contributes to a growing body of evidence suggesting that TfR concentration is not affected by infection or inflammation, and is thus useful in identifying ID in the presence of concurrent infection (33,34). Moreover, the combined measurement of hemoglobin, TfR, ZPP:H, and CRP levels from capillary blood provides a minimally invasive, field-friendly means of accurately detecting ID.

	FOOTNOTES

 
¹ Supported by the National Science Foundation Program in Physical Anthropology (BCS-0200767) and the University of Washington Royalty Research Fund.

³ Abbreviations used: CRP, C-reactive protein; DBS, dried blood spots; Hb, hemoglobin; ID, iron deficiency; IDA. iron deficiency anemia; IDE, iron-deficient erythropoiesis; SF, serum ferritin; sTfR, serum transferrin receptor; TfR, transferrin receptor; ZPP:H, zinc protoporphyrin to heme ratio.

Manuscript received 7 August 2003. Initial review completed 26 September 2003. Revision accepted 12 November 2003.

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