Clinical Infectious Diseases Advance Access published November 26, 2014

1 Complex anemia in tuberculosis: the need to consider causes and timing while

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designing interventions

Peter A. Minchella1, Simon Donkor2, Olumuyiwa Owolabi2, Jayne S. Sutherland2, Joann M. McDermid1

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Vaccinology Theme, Medical Research Council Unit, Fajara, The Gambia

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Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA

Corresponding Author: Joann M. McDermid, Division of Nutritional Sciences, 310

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Savage Hall, Cornell University, Ithaca, NY 14853, Phone: +1-607-255-2490, Fax: +1607-255-1033, Email: [email protected]

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Alternate Corresponding Author: Peter A. Minchella, Division of Nutritional Sciences, 308 Savage Hall, Cornell University, Ithaca, NY 14853, Phone: +1-765-714-5717, Fax:

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+1-607-255-1033

Summary of Main Findings (38 words): Anemia and tuberculosis comorbidity is common, and effective resolution of anemia must link interventions to causes. Inflammation anemia responds to tuberculosis treatment but iron-deficiency anemia

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does not. Monitoring iron-related biomarkers can inform effective and appropriately

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timed anemia interventions.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail: [email protected].

Downloaded from http://cid.oxfordjournals.org/ at Monash University on December 4, 2014

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Abstract

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Background: Anemia is common in tuberculosis and multiple etiologies necessitate

targeted interventions. The proportion of iron-responsive anemia due to iron deficiency compared to iron-unresponsive anemia due to impaired iron absorption/redistribution from tuberculosis-associated immune activation or inflammation is unknown. This

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Methods: Baseline hemoglobin, ferritin, hepcidin, soluble transferrin receptor (sTfR)

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and transferrin were measured in 45 confirmed pulmonary tuberculosis cases, 47 tuberculin skin test (TST)-positive controls and 39 TST-negative controls in The Gambia.

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TB cases were additionally followed two and six months after tuberculosis treatment initiation. Mutually exclusive anemia categories based on iron biomarker concentrations were iron-deficiency anemia (IDA), anemia of inflammation (AI) and multifactorial

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anemia (IDA+AI).

Results: Anemia was more frequent in tuberculosis cases (67%) compared to TSTpositive (36%) or TST-negative (21%) controls. AI was the predominant anemia at tuberculosis diagnosis, declining from 36% to 8% after six months of treatment;

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however, a corresponding reduction was not evident for anemia with iron-responsive components (IDA, IDA+AI). Iron biomarkers discriminated between active tuberculosis

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and TST-positive or TST-negative controls, as well as between active untreated and treated tuberculosis. This was most noticeable for hepcidin, which decreased from a median of 84.0 ng/ml at diagnosis to 9.7 ng/ml after two months (p10mm was

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considered TST-positive (n=47) and ≤10mm TST-negative (n=39) due to Bacille-

Calmette Guerin (BCG) vaccination and high prevalence of environmental mycobacteria in this setting. Sputum samples were stained with auramine and the Ziehl-Nielsen

method. Sputum was decontaminated using N-acetyl cysteine (NALC)-NaOH before

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slopes. Positive cultures were confirmed by Ziehl-Nielsen smear.

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All TB cases underwent a clinical assessment at recruitment (defined as TB diagnosis) and at two and six months following TB treatment initiation. The clinical

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assessment included determination of disease severity by chest x-ray, comorbidity assessment and TB-specific clinical questions such as the presence of side pain, cough duration and weight loss. Malaria screening was conducted using a rapid diagnostic

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test, and those with malaria were excluded from participation. Blood samples were obtained from TB cases at all three time points and at baseline only for TST-positive and TST-negative groups with storage at -70oC until analysis. At the time these data were collected, TB treatment success rate in The Gambia was >85% [26] and national

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TB treatment guidelines included an intensive phase of isoniazid, rifampicin, ethambutol, and pyrazinamide for two months followed by isoniazid and rifampicin for four months

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[27].

Downloaded from http://cid.oxfordjournals.org/ at Monash University on December 4, 2014

culturing in Bactec vials (Becton Dickinson, USA) and on paired Lowenstein-Jensen

7 Demographic, Anthropometric and Clinical Characteristics Data was collected on participant age, gender, body mass index (BMI), mid-

(WBC) and mean corpuscular volume (MCV). Iron Status Biomarkers and Anemia Classification

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upper arm circumference (MUAC), HIV-status, hemoglobin (Hb), white blood cell count

Plasma or serum ferritin (Immuno-biological Laboratories, Germany), soluble

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Technologies, USA) were measured by ELISA. Hepcidin was measured using a

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competitive enzyme immunoassay (Bachem, USA). All biomarker assays were optimized for use with plasma and serum and a sensitivity analysis confirmed specimen

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type did not affect interpretation. Test samples, standards, and controls were assayed in duplicate and concentrations interpolated from 4-parameter logistic standard curves (log/log curves for sTfR). All standard curves were generated using SoftmaxPro 6

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(Molecular Devices, USA). Samples with an intra-assay coefficient of variation >15%, were re-assayed. Lower limits of detection (LoDs) for all assays, with the exception of hepcidin, were defined by the manufacturer. For hepcidin, the LoD (0.2 ng/ml) was interpolated at three standard deviations from the all plate mean (e.g. wells that

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contained diluent in lieu of hepcidin standard or sample). Anemia was defined according to World Health Organization criteria for males Hb

Complex anemia in tuberculosis: the need to consider causes and timing when designing interventions.

Anemia is common in tuberculosis, and multiple etiologies necessitate targeted interventions. The proportion of iron-responsive anemia due to iron def...
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