Relationship Between Blood Concentrations of Hepcidin and Anemia Severity, Mycobacterial Burden, and Mortality Among Patients With HIV-Associated Tuberculosis

The Journal of Infectious Diseases MAJOR ARTICLE Relationship Between Blood Concentrations of Hepcidin and Anemia Severity, Mycobacterial Burden, and Mortality Among Patients With HIV-Associated Tuberculosis Andrew D. Kerkhoff,1,2,3 Graeme Meintjes,4,5,7 Rosie Burton,6 Monica Vogt,3 Robin Wood,3,8 and Stephen D. Lawn3,8 1 Department of Medicine, University of California San Francisco School of Medicine, 2Department of Global Health, Academic Medical Center, Amsterdam Institute for Global Health and Development, University of Amsterdam, The Netherlands; 3The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, 4Department of Medicine, Faculty of Health Sciences, 5 Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, and 6Department of Medicine, Khayelitsha District Hospital, Cape Town, South Africa; 7Department of Medicine, Imperial College, and 8Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom (See the editorial commentary by Armitage and Moran on pages 3–5.) Tuberculosis remains the leading cause of death among people living with human immunodeficiency virus (HIV) globally and accounts for approximately 300 000 AIDS-related deaths each year in sub-Saharan Africa [1]. Among HIV-infected patients, low hemoglobin levels are strongly predictive for tuberculosis [2–4], and anemia is one of the most common complications of both disease processes [5–7]. In patients with HIV-associated tuberculosis, anemia is strongly associated with morbidity and risk of death [8–11]. Thus, there is a need for a better Received 25 February 2015; accepted 22 May 2015; published online 1 July 2015. Correspondence: A. D. Kerkhoff, Department of Medicine, University of California San Francisco School of Medicine, 505 Parnassus Ave, Box 0119, San Francisco, CA 94143 (). The Journal of Infectious Diseases® 2016;213:61–70 © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/infdis/jiv364 understanding of the mechanisms underpinning anemia in such patients so that effective interventions may be designed and implemented. These mechanisms are likely to be multifactorial, although increasing evidence suggests that a majority of patients with HIV-associated tuberculosis have anemia of chronic disease (ACD) with or without an additional etiology [12, 13]. Hepcidin is an acute-phase reactant peptide that is the central regulator of iron homeostasis, and its expression is modulated by several factors, including body iron status and hypoxia [14]. Additionally, infections and inflammation may stimulate hepcidin expression by hepatocytes, a process that is mediated via proinflammatory cytokines, notably interleukin 6 (IL-6), and signaling through the STAT-3 pathway [15, 16]. Hepcidin drives the process of ACD by causing iron to be diverted from the circulation and sequestered within cells of the reticuloendothelial system and by limiting duodenal absorption of iron. Thus, as a consequence of inflammation, hepcidin Blood Hepcidin Concentrations in HIV-Associated Tuberculosis • JID 2016:213 (1 January) • 61 Background. Anemia is very common in patients with human immunodeficiency virus (HIV)–associated tuberculosis, and hepcidin may be key in mediating this. We explored the relationship between blood hepcidin concentrations and anemia severity, mycobacterial burden and mortality in patients with HIV-associated tuberculosis. Methods. Consecutive unselected HIV-infected adults in South Africa were systematically investigated for tuberculosis. Three groups were studied: 116 hospitalized inpatients with HIV infection and tuberculosis (hereafter, “hospitalized patients”), 58 ambulatory outpatients with HIV infection and newly diagnosed tuberculosis (hereafter, “ambulatory patients with tuberculosis”), and 58 ambulatory outpatients with HIV infection and without tuberculosis (hereafter, “ambulatory patients without tuberculosis”). Blood hepcidin concentrations were determined for all patients. Vital status at 3 months was determined, and independent predictors of mortality were identified. Results. Median hepcidin concentrations were 38.8 ng/mL among hospitalized patients, 19.1 ng/mL among ambulatory patients with tuberculosis, and 5.9 ng/mL among ambulatory patients without tuberculosis (P < .001). In both groups with HIV-associated tuberculosis, hepcidin concentrations were strongly associated with greater anemia severity. Additionally, strong, graded associations were observed between hepcidin and composite indices of mycobacterial burden and dissemination. Patients dying within 3 months had significantly higher hepcidin concentrations, which independently predicted mortality. Conclusions. High hepcidin concentrations were strongly associated with disseminated disease, anemia, and poor prognosis in patients with HIV-associated tuberculosis. Hepcidin may be a mechanistically important mediator underlying the high prevalence of severe anemia in these patients. Keywords. HIV; AIDS; tuberculosis; anemia; hepcidin; antimicrobial; Africa. METHODS This study comprised hospitalized inpatients with HIV infection and newly diagnosed tuberculosis (hereafter, “hospitalized patients”), ambulatory antiretroviral therapy (ART)–naive outpatients with HIV infection and newly diagnosed tuberculosis (hereafter, “ambulatory patients with tuberculosis”), and ambulatory ART-naive outpatients with HIV infection and without tuberculosis (hereafter, “ambulatory patients without tuberculosis”). All patients were unselected and consecutively recruited as part of two previously reported studies of tuberculosis diagnostic analyses [23, 24], and most resided in the township communities of Cape Town, where there is a large tuberculosis burden [25, 26]. These studies were approved by the research ethics committees of the University of Cape Town and the London School of Hygiene and Tropical Medicine. All patients provided written informed consent. Hospitalized patients were drawn from among HIV-infected patients from the same township communities who were admitted to medical wards at G. F. Jooste Hospital, ≥18 years old, without a tuberculosis diagnosis prior to admission, and systematically and thoroughly screened for tuberculosis regardless of clinical presentation [24]. These patients were eligible for inclusion in the present study if they were found to have a new microbiologically confirmed diagnosis of tuberculosis, had a frozen plasma sample available for laboratory measurements, and had not had a blood tra (...truncated)