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Chronic Bronchitis

Person Janet R Gilsdorf, M.D.
Article Reference Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease.
Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. COPD is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non-typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis.
Article Reference Collaborative studies in mucosal immunology in Goroka.
A collaborative program between the Papua New Guinea (PNG) Institute of Medical Research and the Hunter Mucosal Group has completed studies relevant to protection of the airways against bacterial infection. Specifically, these studies addressed the mucosal capacity to produce local immunoglobulins and the capacity of the airways to respond to an oral vaccine containing inactivated nontypeable Haemophilus influenzae (NTHi). The mucosal IgA response to NTHi antigens was blunted in both children and adults in PNG compared with that found in Australian children and adults, whose airways are colonized only intermittently. Despite this, when oral NTHi is given to Papua New Guinean adults with chronic airways disease, it is followed by a significant (50%) reduction in incidence of acute bronchitic episodes, and a 3-log reduction in density of colonization, which persisted about 10 months. The implications of these key findings are discussed with respect to both mechanism and wider control of pathology emanating from abnormal airways colonization in a PNG environment.
Article Reference Comparison study of single and concurrent administrations of carbapenem, new quinolone, and macrolide against in vitro nontypeable Haemophilus influenzae mature biofilms.
Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen and a common cause of otitis media in children, chronic bronchitis, and pneumonia in patients with chronic obstructive pulmonary disease. Many studies have reported that NTHi is capable of producing biofilms, which may be one of the important factors involved in chronic diseases and accelerating antimicrobial resistance. Unfortunately, there is still no consensus about the elimination of biofilms. In this study, concurrent administrations of levofloxacin (LVFX)-imipenem (IPM) and clarithromycin (CAM)-IPM, as well as the single administration of IPM, LVFX, and CAM, were performed to treat the mature biofilms produced by NTHi, respectively. Biofilm inhibition was quantified using microtiter biofilm assay (MBA), and relative biomass was calculated as the ratio compared to that of untreated control biofilms. The relative biomasses of biofilms treated with IPM, LVFX-IPM, and CAM-IPM against a β-lactamase-negative ampicillin-resistant strain was 1.10, 0.08, and 0.13 at 1× minimum inhibitory concentration (MIC), 0.90, 0.05, and 0.07 at 10× MIC, and 0.80, 0.06, and 0.07 at 100× MIC, respectively. Biofilms were also visually observed by scanning electron microscopy, and a focused ion-beam system showed that high concentrations of combined administration strongly inhibited the biofilms, which was consistent with the results of MBA. Our data demonstrated the antibiofilm effect of concurrent administration against mature NTHi biofilms, which indicated a rationale for the potential use of concurrent administrations in diseases involving chronic NTHi biofilms.
Article Reference Streptococcus pneumoniae and non-typable Haemophilus influenzae causing bacterial bronchitis in children and the impact of vaccination.
ABSTRACT BACKGROUND: Protracted bacterial bronchitis is a major cause of persistent cough in childhood. The organisms most commonly isolated are non-typable Haemophilus influenzae [NTHi] and Streptococcus pneumoniae [SP]. There are no studies addressing typing of these organisms when recovered from the lower airways. METHODS: Isolates of these two organisms identified in bronchoalveolar lavage (BAL) samples from children undergoing routine investigation of a chronic cough thought to be attributable to a protracted bacterial bronchitis were subject to typing. Samples were collected in Sheffield, UK and Athens, Greece. The majority of the children from Sheffield had received PCV-7 or PCV-13 conjugate vaccine but only a minority of Greek children had received the PCV-7 vaccine. RESULTS: All 18 SP isolates from Greek BAL samples are serotypes contained in PCV-13 while 10 are contained in PCV-7. In contrast, 28 of the 39 samples from Sheffield contained serotypes that are not included in PCV-13. All 26 of the NTHi samples obtained in Sheffield produced distinct MLVA profiles. There was a significant difference between children from Athens and Sheffield in the distribution of serotypes contained or not in the pneumococcal vaccine (p=0.04). More specifically, immunisation with pneumococcal vaccine was related with isolation of S. pneumoniae serotypes not included in the vaccine [OR: 0.021, CI: 0.003-0.115, p<0.001]. CONCLUSIONS: The data suggests that both vaccine and non-vaccine Strep. pneumoniae serotypes may play a role in protracted bacterial bronchitis and provide some hints that serotype replacement may occur in response to the introduction of conjugate vaccines.Dept. Of Respiratory Medicine, Sheffield Children's Hospital, Sheffield, S10 2TH UK*Third Dept. of Paediatrics, ``Attikon'' Hospital, University of Athens School of Medicine, Athens, Greece 1 Rimini Str, Chaidari 12464, Greece# Respiratory & Systemic Infection Laboratory, Health Protection Agency, Microbiology Services Division Colindale, 61 Colindale Avenue, London NW9 5HT, UK$Respiratory Unit, Dept of Paediatrics, University of Patras, Patra, Greece^Microbiology Dept. Royal Hallamshire Hospital, Sheffield, S10 2JFUK∼Microbiology Dept, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH@National Meningitis Reference Laboratory, National School of Public Health, Athens, Greece,+Dept. of Pediatrics, University of Thessaly, School of Medicine, General University Hospital of Larissa, Greece%Dept. of Clinical Microbiology, Penteli Children's Hospital, Athens, Greece,Corresponding author: Prof. Mark Everard, Dept. of Respiratory Medicine, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH UK, Email: m.l.everard@sheffield.ac.uk.
Article Reference Characterization of extended co-culture of non-typeable Haemophilus influenzae with primary human respiratory tissues.
Non-typeable Haemophilus influenzae (NTHi) are human-adapted Gram-negative bacteria that comprise part of the normal flora of the human upper airway, but are also responsible for a number of mucosal infections such as otitis media and bronchitis. These infections often recur and can become chronic. To characterize the effect of long-term co-culture of NTHi with human tissues, we infected primary respiratory epithelial cells grown at the air-liquid interface with three NTHi strains over a range of 1-10 days. Scanning and transmission electron microscopy of tissues confirmed that intact NTHi were persisting paracellularly, while organisms observed in intracellular vacuoles appeared degraded. Furthermore, the apical surface and tight junctions of the infected tissues were undisturbed, with high transepithelial electrical resistances, while the basal cell layer displayed more junctional disorganization and wider intercellular spaces than the uninfected control tissues. Although the tissues elaborated the cytokine profile reported for NTHi-caused otitis media in vivo, there was little change in the dynamics of cytokine secretion over the time points tested. Finally, we report that NTHi strains released outer membrane vesicles (OMVs) during extended co-culture with the tissues, and show that these OMVs directly interact with host cell membranes.
Article Reference Regulation of the vapBC-1 toxin-antitoxin locus in nontypeable Haemophilus influenzae.
Nontypeable Haemophilus influenzae (NTHi) are human-adapted commensal bacteria that can cause a number of chronic mucosal infections, including otitis media and bronchitis. One way for these organisms to survive antibiotic therapy and cause recurrent disease is to stop replicating, as most antimicrobials target essential biosynthetic pathways. Toxin-antitoxin (TA) gene pairs have been shown to facilitate entry into a reversible bacteriostatic state. Characteristically, these operons encode a protein toxin and an antitoxin that associate following translation to form a nontoxic complex, which then binds to and regulates the cognate TA promoter. Under stressful conditions, the labile antitoxin is degraded and the complex disintegrates, freeing the stable toxin to facilitate growth arrest. How these events affected the regulation of the TA locus, as well as how the transcription of the operon was subsequently returned to its normal state upon resumption of growth, was not fully understood. Here we show that expression of the NTHi vapBC-1 TA locus is repressed by a complex of VapB-1 and VapC-1 under conditions favorable for growth, and activated by the global transactivator Factor for Inversion Stimulation (Fis) upon nutrient upshift from stationary phase. Further, we demonstrate for the first time that the VapC-1 toxin alone can bind to its cognate TA locus control region and that the presence of VapB-1 directs the binding of the VapBC-1 complex in the transcriptional regulation of vapBC-1.
Article Reference Towards a vaccine for chronic obstructive pulmonary disease.
This review discusses chronic obstructive pulmonary disease as an outcome of two pathogenic pathways: the first resulting from inhalation of toxins and the second a consequence of bacterial colonisation of damaged airways. Earlier assessment of the role played by bacteria in acute exacerbations was compromised by a deficiency of quality data and the use of parameters more relevant to invasive infection. Data are reviewed to support a hypothesis that states intrabronchial inflammation reflects an excessive and inappropriate host response (largely mediated by Th17 cells derived from gut-associated lymphoid tissues) to colonising bacteria acting as an 'antigen sump' (in essence, a hypersensitivity reaction). It is proposed that both viral and bacterial infections exacerbate inflammation through a common pathway that involves colonising bacteria. An oral vaccine containing inactivated non-typeable Haemophilus influenzae augments a protective loop that involves the aspiration of bronchus content into the gut and reduces the severity of acute exacerbations including the need for hospital admission by reducing the 'load' of bacteria comprising this final common path. The positive clinical results from trials using oral NTHi support both the concept that bacterial colonisation of damaged airways is a potent second pathogenic pathway and that oral immunotherapy provides a significant therapeutic advance in limiting damage in chronic obstructive pulmonary disease.
Article Reference Bronchoscopic findings in children with chronic wet cough.
Protracted bacterial bronchitis is defined as the presence of more than 4 weeks of chronic wet cough that resolves with appropriate antibiotic therapy, in the absence of alternative diagnoses. The diagnosis of protracted bacterial bronchitis is not readily accepted within the pediatric community, however, and data on the incidence of bacterial bronchitis in children are deficient. The objective of this study was to determine the frequency of bacterial bronchitis in children with chronic wet cough and to analyze their bronchoscopic findings.
Article Reference Murine model of chronic respiratory inflammation.
The respiratory mucosa is exposed to the external environment each time we breathe and therefore requires a robust and sophisticated immune defense system. As with other mucosal sites, the respiratory mucosal immune system must balance its response to pathogens while also regulating inflammatory immune cell-mediated tissue damage. In the airways, a failure to tightly control immune responses to a pathogen can result in chronic inflammation and tissue destruction with an overzealous response being deleterious for the host. Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the US and both the prevalence of and mortality rate of this disease is increasing annually. COPD is characterized by intermittent disease exacerbation. The causal contribution of bacterial infections to exacerbations of COPD is now widely accepted, accounting for at least 50% of all exacerbations. Non-typeable Haemophilus influenzae and Moraxella catarrhalis (both gram-negative bacteria) along with Streptococcus pneumoniae (a gram-positive bacterium) are the three most common bacterial pathogens that cause respiratory tract infections in COPD patients. The colonization of bacteria in the lower airways is similar to a low-grade smoldering infection that induces chronic airway inflammation. Chronic low-grade infection can induce a persistent inflammatory response in the airways and parenchyma. Inefficient removal of bacteria from the lower respiratory tract is characteristic of chronic bronchitis. Inflammation is believed to be central to the pathogenesis of exacerbations, but a clear understanding of the inflammatory changes during an exacerbation of COPD has yet to emerge. As bacterial colonization of the lung in COPD patients is a chronic inflammatory condition highlighted by frequent bouts of exacerbation and clearance, we sought to reproduce this chronic pathogen-mediated inflammation in a murine model by repeatedly delivering the intact, whole, live bacteria intra-tracheally to the lungs.
Article Reference Haemophilus influenzae and smoking-related obstructive airways disease.
Intralumenal bacteria play a critical role in the pathogenesis of acute infective episodes and airway inflammation. Antigens from colonizing bacteria such as nontypeable Haemophilus influenzae (NTHi) may contribute to chronic lung disease through an immediate hypersensitivity response. The objective of this study was to determine the presence of specific NTHi-IgE antibodies in subjects with chronic bronchitis (CB) and COPD who had smoked.
Article Reference Nrf2 regulates chronic lung inflammation and B-cell responses to nontypeable Haemophilus influenzae.
Nrf2 is a leucine zipper transcription factor that protects against oxidant-induced injury. Nontypeable Haemophilus influenzae is responsible for frequent disease exacerbations in patients with chronic obstructive pulmonary disease and is responsible for causing otitis media in young children. We hypothesized that Nrf2 would limit inflammatory responses to nontypeable H. influenzae. The objective of this study was to assess the role of Nrf2 in chronic lung inflammation and regulation of immune responses to nontypeable H. influenzae in mice. Wild-type (C57BL/6) mice and Nrf2(-/-) mice were instilled by oropharyngeal aspiration of 1 × 10(6) colony-forming units of live, nontypeable H. influenzae (NTHI) twice a week for 4 to 16 consecutive weeks to generate a chronic inflammatory milieu within the lungs that models chronic bronchitis. Nrf2(-/-) mice had increased lymphocytic airway inflammation compared with WT mice after NTHI challenge. Although the extent of NTHI-induced peribronchovascular inflammation did not significantly differ between the genotypes, plasma cell infiltration was significantly more abundant in Nrf2(-/-) mice. Most strikingly, Nrf2(-/-) mice generated significantly enhanced and persistent levels of serum antibodies against P6, a key outer membrane protein of NTHI. Lung dendritic cells from Nrf2(-/-) mice challenged with NTHI had increased activation markers compared with dendritic cells from similarly treated WT mice. Nrf2 regulates NTHI-induced airway inflammation characterized by lymphocytic and plasma cell infiltration and the activation of lung dendritic cells and B-cell responses in mice. Nrf2 may be a potential therapeutic target in limiting the bacterial infection-induced airway inflammation that drives exacerbations of chronic obstructive pulmonary disease.
Article Reference Acute exacerbations in COPD and their control with oral immunization with non-typeable haemophilus influenzae.
Chronic obstructive pulmonary disease (COPD) a term based on the demonstration of irreversible airways obstruction, introduced to unify a range of chronic progressive diseases of the airways consequent upon inhalation of toxins. While disease is initiated and progressed by inhaled toxins, an additional pathway of damage has emerged, with particular relevance to acute exacerbations. Exacerbations of disease due to an increase in the level of intrabronchial inflammation have taken on a new significance as their role in determining both acute and chronic outcomes is better understood. This ``second pathway'' of disease is a consequence of bacterial colonization of damaged airways. Although bacteria have been linked to acute episodes in COPD over 50 years, only recently has quality data on antibiotic usage and the detection of ``exacerbation isolates'' of non-typeable Haemophilus influenzae (NTHi) provided strong argument in support of a pathogenic role. Yet a poor correlation between detection of colonizing bacteria and clinical status remained a concern in attempts to explain a role for bacteria in a classical infection model. This presentation discusses a hypothesis that acute exacerbations reflect a T cell-dependent hypersensitivity response to colonizing bacteria, with IL-17 dependent accumulation of neutrophils within the bronchus, as the main outcome measure. Critical protection against exacerbations following oral administration of NTHi, an immunotherapy that drives a TH17 T cell response from Peyer's patches, reduces the load of intrabronchial bacteria while preventing access of inhaled bacteria into small airways. Immunotherapy augments a physiological ``loop'' based on aspiration of bronchus content into the gut. A second ``hypersensitivity'' mechanism may cause bronchospasm - in both COPD and treatment-resistant asthma - due to specific IgE antibody directed against colonizing bacteria, as oral NTHi abrogates wheeze in subjects with recurrent ``wheezy bronchitis.''
Article Reference Oral non-typable Haemophilus influenzae enhances physiological mechanism of airways protection.
Oral immunotherapy with inactivated non-typeable Haemophilus influenzae (NTHi) prevents exacerbations of chronic obstructive pulmonary disease, but the mechanism is unclear. The aim of this study was to determine the mechanism of protection. This was a placebo versus active prospective study over 3 months in 64 smokers. The active treatment was three courses of oral NTHi given at monthly intervals, followed by measurement of bacteriological and immunological parameters. The results can be summarized: (i) NTHi-specific T cells increased in the placebo treatment group over time (P<0.05); (ii) the T cell response in the oral NTHi group started earlier than that in the placebo group (P<0.05); and (iii) serum NTHi-specific immunoglobulin (Ig)G had significantly greater variation in the placebo group (P<0.0001). The increase in antibody in placebos over time correlated with exposure to live H. influenzae (P<0.05) determined from culture of gargles; (iv) reduction in saliva lysozyme over time (P<0.05) was detected only in the oral NTHi treatment group. These data are consistent with T cell priming of gut lymphoid tissue by aspiration of bronchus content into the gut, with oral immunotherapy augmenting this process leading to enhanced bronchus protection. The evidence for protection was a stable IgG antibody level through the study in the oral NTHi treatment group, contrasting with an increase in antibody correlating with exposure of the airways to H. influenzae in the placebo group. Saliva lysozyme was a useful biomarker of mucosal inflammation, falling after oral NTHi consistent with a reduction in the level of intralumenal inflammation.
Article Reference Cytotoxic T lymphocyte and natural killer cell responses to non-typeable Haemophilus influenzae.
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have a key role in host defence against infectious pathogens, but their response to bacteria is not well characterized. Non-typeable Haemophilus influenzae is a major cause of respiratory tract infection including otitis media, sinusitis, tonsillitis and chronic bronchitis (especially in chronic obstructive pulmonary disease and bronchiectasis). This bacterium is also present in the pharynx of most healthy adults. The primary factor that may determine whether clinical disease occurs or not is the nature of the lymphocyte response. Here we examined the CTL cell and NK cell responses to nontypeable H. influenzae in healthy control subjects and in subjects who had bronchiectasis and recurrent bronchial infection with this bacterium. Cells were stimulated with live H. influenzae and intracellular cytokine production and release of cytotoxic granules measured. Control subjects had significantly higher levels of interferon gamma production by both CTL and NK cells, while levels of cytotoxic granule release were similar in both groups. The main lymphocyte subsets that proliferated in response to H. influenzae stimulation were the CTL and NK cells. The results suggest that CTL and NK cell responses may be important in preventing disease from nontypeable H. influenzae infection.
Article Reference [Immunity to antigens of nontypeable Haemophilus influenzae strains].
Nonencapsulated (nontypeable) Haemophilus influenzae (NTHi) is a Gram-negative coccobacillus colonizing upper respiratory tract of most healthy people and causing such diseases as otitis media, sinusitis, exacerbations of chronic obstructive pulmonary disease, and bronchitis. NTHi may cause systemic infection. As a result, over the past decade the bacterium has been the subject of intense research. However immune response to NTHi has not been well characterized. Data on research of immune response to NTHi are presented.
Article Reference Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and Diminish established biofilms.
Nontypeable Haemophilus influenzae (NTHi) commonly causes otitis media, chronic bronchitis in emphysema, and early airway infections in cystic fibrosis. Long-term, low-dose azithromycin has been shown to improve clinical outcomes in chronic lung diseases, although the mechanism of action remains unclear. The inhibition of bacterial biofilms by azithromycin has been postulated to be one mechanism mediating these effects. We hypothesized that subinhibitory concentrations of azithromycin would affect NTHi biofilm formation. Laboratory strains of NTHi expressing green fluorescent protein and azithromycin-resistant clinical isolates were grown in flow-cell and static-culture biofilm models. Using a range of concentrations of azithromycin and gentamicin, we measured the degree to which these antibiotics inhibited biofilm formation and persistence. Large biofilms formed over 2 to 4 days in a flow cell, displaying complex structures, including towers and channels. Subinhibitory concentrations of azithromycin significantly decreased biomass and maximal thickness in both forming and established NTHi biofilms. In contrast, subinhibitory concentrations of gentamicin had no effect on biofilm formation. Furthermore, established NTHi biofilms became resistant to gentamicin at concentrations far above the MIC. Biofilm formation of highly resistant clinical NTHi isolates (azithromycin MIC of > 64 microg/ml) was similarly decreased at subinhibitory azithromycin concentrations. Clinically obtainable azithromycin concentrations inhibited biofilms in all but the most highly resistant isolates. These data show that subinhibitory concentrations of azithromycin have antibiofilm properties, provide mechanistic insights, and supply an additional rationale for the use of azithromycin in chronic biofilm infections involving H. influenzae.
Article Reference Characterization of the N-acetyl-5-neuraminic acid-binding site of the extracytoplasmic solute receptor (SiaP) of nontypeable Haemophilus influenzae strain 2019.
Nontypeable Haemophilus influenzae is an opportunistic human pathogen causing otitis media in children and chronic bronchitis and pneumonia in patients with chronic obstructive pulmonary disease. The outer membrane of nontypeable H. influenzae is dominated by lipooligosaccharides (LOS), many of which incorporate sialic acid as a terminal nonreducing sugar. Sialic acid has been demonstrated to be an important factor in the survival of the bacteria within the host environment. H. influenzae is incapable of synthesizing sialic acid and is dependent on scavenging free sialic acid from the host environment. To achieve this, H. influenzae utilizes a tripartite ATP-independent periplasmic transporter. In this study, we characterize the binding site of the extracytoplasmic solute receptor (SiaP) from nontypeable H. influenzae strain 2019. A crystal structure of N-acetyl-5-neuraminic acid (Neu5Ac)-bound SiaP was determined to 1.4A resolution. Thermodynamic characterization of Neu5Ac binding shows this interaction is enthalpically driven with a substantial unfavorable contribution from entropy. This is expected because the binding of SiaP to Neu5Ac is mediated by numerous hydrogen bonds and has several buried water molecules. Point mutations targeting specific amino acids were introduced in the putative binding site. Complementation with the mutated siaP constructs resulted either in full, partial, or no complementation, depending on the role of specific residues. Mass spectrometry analysis of the O-deacylated LOS of the R127K point mutation confirmed the observation of reduced incorporation of Neu5Ac into the LOS. The decreased ability of H. influenzae to import sialic acid had negative effects on resistance to complement-mediated killing and viability of biofilms in vitro, confirming the importance of sialic acid transport to the bacterium.
Article Reference Nontypeable Haemophilus influenzae: understanding virulence and commensal behavior.
Haemophilus influenzae is genetically diverse and exists as a near-ubiquitous human commensal or as a pathogen. Invasive type b disease has been almost eliminated in developed countries; however, unencapsulated strains - nontypeable H. influenzae (NTHi) - remain important as causes of respiratory infections. Respiratory tract disease occurs when NTHi adhere to or invade respiratory epithelial cells, initiating one or more of several proinflammatory pathways. Biofilm formation explains many of the observations seen in chronic otitis media and chronic bronchitis. However, NTHi biofilms seem to lack a biofilm-specific polysaccharide in the extracellular matrix, a source of controversy regarding their relevance. Successful commensalism requires dampening of the inflammatory response and evasion of host defenses, accomplished in part through phase variation.
Article Reference The OxyR regulon in nontypeable Haemophilus influenzae.
Nontypeable Haemophilus influenzae (NTHi) is a gram-negative bacterium and a common commensal organism of the upper respiratory tract in humans. NTHi causes a number of diseases, including otitis media, sinusitis, conjunctivitis, exacerbations of chronic obstructive pulmonary disease, and bronchitis. During the course of colonization and infection, NTHi must withstand oxidative stress generated by insult due to multiple reactive oxygen species produced endogenously by other copathogens and by host cells. Using an NTHi-specific microarray containing oligonucleotides representing the 1821 open reading frames of the recently sequenced NTHi isolate 86-028NP, we have identified 40 genes in strain 86-028NP that are upregulated after induction of oxidative stress due to hydrogen peroxide. Further comparisons between the parent and an isogenic oxyR mutant identified a subset of 11 genes that were transcriptionally regulated by OxyR, a global regulator of oxidative stress. Interestingly, hydrogen peroxide induced the OxyR-independent upregulation of expression of the genes encoding components of multiple iron utilization systems. This finding suggested that careful balancing of levels of intracellular iron was important for minimizing the effects of oxidative stress during NTHi colonization and infection and that there are additional regulatory pathways involved in iron utilization.