Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

Sorrel Ml Namaste, Fabian Rohner, Jin Huang, Nivedita L Bhushan, Rafael Flores-Ayala, Roland Kupka, Zuguo Mei, Rahul Rawat, Anne M Williams, Daniel J Raiten, Christine A Northrop-Clewes, Parminder S Suchdev, Sorrel Ml Namaste, Fabian Rohner, Jin Huang, Nivedita L Bhushan, Rafael Flores-Ayala, Roland Kupka, Zuguo Mei, Rahul Rawat, Anne M Williams, Daniel J Raiten, Christine A Northrop-Clewes, Parminder S Suchdev

Abstract

Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation.Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects.Design: Cross-sectional data from 15 surveys for PSC (n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 μg/L in PSC and <15 μg/L in WRA) in inflammation and malaria settings as follows: 1) increase ferritin-concentration cutoff to <30 μg/L; 2) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L; 3) apply arithmetic correction factors; and 4) use a regression correction approach.Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7-25 and 2-8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores.Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute-phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation.

Keywords: anemia; ferritin; inflammation; iron deficiency; meta-analysis; nutritional assessment.

Figures

FIGURE 1
FIGURE 1
Estimated prevalence [% (95% CI)] of depleted iron stores in preschool children by CRP (A) and AGP (B) deciles: the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. The analysis was restricted to countries (Bangladesh, Cameroon, Côte d’Ivoire, Kenya 2007, Kenya 2010, Laos, Liberia, and Philippines) that measured both CRP and AGP for comparability between CRP and AGP relations with depleted iron stores. Sample size: n = 8458. Depleted iron stores were defined as a ferritin concentration <12 μg/L. Bold vertical lines indicate the commonly used cutoffs for CRP and AGP. AGP, α-1-acid glycoprotein; CRP, C-reactive protein.
FIGURE 2
FIGURE 2
Estimated prevalence [% (95% CI)] of depleted iron stores in women of reproductive age by CRP (A) and AGP (B) deciles: the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. The analysis was restricted to countries (Cameroon, Côte d’Ivoire, Laos, and Liberia) that measured both CRP and AGP for comparability between CRP and AGP relations with depleted iron stores. Sample size: n = 4352. Depleted iron stores were defined as a ferritin concentration <15 μg/L. Bold vertical lines indicate the commonly used cutoffs for CRP and AGP. AGP, α-1-acid glycoprotein; CRP, C-reactive protein.
FIGURE 3
FIGURE 3
Estimated prevalence [% (95% CI)] of depleted iron stores on the basis of internal regression correction adjusting for CRP, AGP, or both in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Depleted iron stores were defined as a ferritin concentration P < 0.0001]; and α-1-acid glycoprotein = −0.52 ln(g/L)] [QE (df = 10) = 584.6, P < 0.0001]. Bars without a common lowercase letter within a given survey differ, P < 0.05 (adjusted by using Bonferroni correction). AGP, α-1-acid glycoprotein; CRP, C-reactive protein.
FIGURE 4
FIGURE 4
Estimated prevalence [% (95% CI)] of depleted iron stores with the use of different inflammation-adjustment approaches in preschool children: BRINDA project. Depleted iron stores were defined as a ferritin concentration P < 0.05 (adjusted by using Bonferroni correction). BRINDA correction factors were as follows—incubation phase: 0.68 (95% CI: 0.60, 0.79); early convalescence phase: 0.38 (95% CI: 0.30, 0.49); and late convalescence phase: 0.65 (95% CI: 0.58, 0.74) [QE (df = 28) = 515.9, P < 0.0001]. Internal regression correction and BRINDA regression correction reference values were as follows—CRP: −2.26 ln(mg/L) [QE (df = 10) = 439.9, P < 0.0001]; and AGP: −0.52 ln(g/L) [QE (df = 10) = 584.6, P < 0.0001]. BRINDA regression correction coefficients were as follows—ln CRP = 0.12 and ln AGP = 0.71 [QE (df = 21) = 644.8, P < 0.0001]. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; -CRP+AGP, adjusting for C-reactive protein and α-1-acid glycoprotein.
FIGURE 5
FIGURE 5
Estimated prevalence [% (95% CI)] of depleted iron stores with the use of different inflammation-adjustment approaches in women of reproductive age: BRINDA project. Depleted iron stores were defined as a ferritin concentration P < 0.05 (adjusted by using Bonferroni correction). BRINDA correction factors were as follows—incubation phase: 0.66 (95% CI: 0.53, 0.83); early convalescence phase: 0.52 (95% CI: 0.44, 0.61); and late convalescence phase: 0.82 (95% CI: 0.68, 0.99) [QE (df = 12) = 38.7, P < 0.0001]. Internal regression correction and BRINDA regression correction reference values were as follows—CRP: −1.83 ln(mg/L) [QE (df = 6) = 1142.4, P < 0.001]; and AGP-0.63 ln(g/L) [QE (df = 4) = 83.8, P < 0.0001]. BRINDA regression correction coefficients were as follows—ln CRP = 0.11; and ln-AGP: 0.34 [QE (df = 9) = 29.6, P < 0.001]. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; -CRP+AGP, adjusting for C-reactive protein and α-1-acid glycoprotein.
FIGURE 6
FIGURE 6
Estimated prevalence [% (95% CI)] of depleted iron stores with the use of different inflammation- and malaria-adjustment approaches in preschool children (A) and women of reproductive age (B): Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Depleted iron stores were defined as a ferritin concentration P < 0.05 (adjusted by using Bonferroni correction). -CRP+AGP, adjusting for C-reactive protein and α-1-acid glycoprotein; -CRP+AGP+malaria, adjusting for C-reactive protein, α-1-acid glycoprotein, and malaria.

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