DOI: 10.31038/IMROJ.2017214

Abstract

Background: Iron is a pro-oxidant and an essential nutrient for different bacteria. Experimental animal studies have demonstrated exacerbating sepsis episodes. Intravenous iron treatment has been implicated, at least theoretically in increasing infection episodes. However, these studies did not obtain any conclusion in this respect. Therefore, the aim of our study was to evaluate whether there is a risk between intravenous iron treatment and infection episodes following iron treatment.

Methods: In our study, 186 patients who received intravenous iron treatment were included. The biochemical parameters included “pre and post iron treatment” (e.g., ferritin, serum iron, transferring saturation, and hemoglobin) and the later emergence of infections. Moreover, we evaluated all possible risk factors that could interfere with the subsequence appearance of infection.

Results: Infectious complications were reported in 24 patients (12.8%) after the iron treatments began, and no infection was reported in 87.15% (n=162) of the patients. The most common infections were urinary (33%) and respiratory infections (25%). The most common infectious agents were enterobacteriae (e.g., E coli, E faecalis, and E faecium). Notably, we did not observe any intracellular pathogens. In our statistical survey, we did not find a relationship between infection onset and intravenous iron treatment. To analyze the baseline disease, comorbidities, such as diabetes and other treatment (e.g., corticosteroids or anti-TNF) were evaluated, and, no association was found.

Conclusion: In our study, intravenous iron was an effective treatment to correct anemia, and it did not appear to correlate with the development of secondary infections.

Key words

iron therapy; intravenous iron; iron infection

Abbreviations

IV – intravenous; HD – hemodialysis infection

Introduction

Iron is an important nutrient for many bacteria, and in laboratory animals, it was shown to exacerbate sepsis. [1] It has been postulated that increased plasma iron is responsible for the association of hemochromatosis with infections by Vibrio vulnificus, Yersinia enterocolitica, and Escherichia coli. [2] Accordingly, there are host defense mechanisms that tend to restrict the available iron from invading pathogens. [3] For example, the transferrin receptor is the major pathway for delivery of iron to peripheral tissues through endocytosis of its ligand, transferrin, which binds to iron and circulates in the plasma. Down regulation of the transferrin receptor limits the cell’s ability to acquire transferrin-bound iron and concomitantly reduces the endosomal pool of iron that can be accessed by intracellular pathogens, such as L. pneumophila, Mycobacterium tuberculosis, and Mycobacterium avium, and thus restricts their growth. [4, 5] Iron repletion with oral iron has been associated with adverse outcomes for certain infections. In a study of 137 iron-deficient Somali nomads, who were treated with placebo or oral iron (71 subjects), Murray et al. noted seven infection episodes in the placebo group and 36 in the oral iron group (including reactivation of preexisting malaria, brucellosis, and tuberculosis). [6] A large iron supplementation trial of young children on Pemba Island, was prematurely terminated as a result of an excess of serious adverse events (including deaths) in those receiving iron. [7] Ferric iron (Fe)–carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. [8] Intravenous (IV) Fe is generally well tolerated and effective in correcting Fe-deficient states. However, complexing Fe to carbohydrate polymers does not block its potent pro-oxidant effects; therefore, systemic free radical generation and, possibly, tissue damage may result. [9] On the other hand, excessive iron administration may lead to oversaturation of transferrin and the release of free, catalytically active iron into circulation (NTBI) [10] which could be readily utilized by bacteria, leading to their multiplication and the possibility of an overwhelming infection. [11, 12] The aim of the present work was to determine the short-term infection rate associated with IV iron treatment and the possible risk factors that can predict these infections in a contemporary patient cohort.

Material and methods

Patient enrollment A retrospective, longitudinal study was carried out at Marqués de Valdecilla University Hospital (Santander, Spain). The hospital records of patients who underwent ambulatory treatment with IV iron at the hospital day center between January 2011 and December 2012 were reviewed.

Patient parameter evaluation The medical records of these patients were searched after institutional review board approval was obtained for the following data fields: a) demographic features; b) principal diagnosis; c) comorbid factors, such as diabetes mellitus, arterial hypertension, and dislipemia; d) concomitant treatment as potential infection causes, such as corticosteroids, immunosuppresive therapy, and anti-TNF treatment; e) previous infection, and; f) laboratory data prior to and after IV iron treatment, such as hemoglobin concentration, mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), red cell volume distribution width (RDW), serum iron, transferrin saturation, and serum ferritin.

Intravenous iron treatment One thusand mg (50 mg/ml) of ferric carboxymaltose was administered in an ambulatory regimen to the subjects at the hospital day center. The doses of this treatment were adapted subsequently according to the Ganzoni equation and their efficacy.

Case definitions We used a retrospective cohort design with a 1-month baseline period. After IV iron treatment was started, all of the patients were followed for 3 months. We looked for any infectious diseases, and we differentiated the subjects by bacterial, viral and fungal infections, as well as by gastrointestinal, genitourinary, respiratory and other diseases. If a single blood culture was positive for coagulase-negative staphylococci, Corynebacteria, or Bacillus sp., the culture was considered contaminated or representative of a transient bacteremia but not of a bacteremic episode. All other situations in patients in whom at least one blood culture was positive were defined as bacteremic episodes.

Statistical Analysis The results were analyzed with the SPSS 15.0 computer software package (Statistical Package for Social Sciences, Inc., Chicago. IL). Continuous variables were summarized as the means or as the medians and ranges. Categorical variables were compared with the chi-square and Fisher´s exact tests. Correlations between the data sets were examined using the Pearson (r) or Spearman rank (rs) correlation coefficients. Any differences were considered significant for all statistical tests at p values of less than 0.05.

Results

A total of 186 adult patients (70 men and 116 women; mean age, 63 yrs; range, 18 to 80 yrs) were enrolled. The principal diagnosis of the patients included in the study were cardiac diseases (n=41, 22%), neoplasm diseases (n=32, 17.2%), renal diseases (n=31, 16.7%), malnutrition due to bariatric surgery (n=19, 10.2%), hepatic diseases (n=15, 8.1%), and lung diseases (n=15, 8.1%) (Table 1). A comorbid condition known to increase the infection risk was found in 88 patients (47.3%), which included diabetes mellitus (n = 53), current malignancy (n = 32) (under treatment and/or not cured), being a transplant recipient (n= 3), and having both a malignancy and diabetes mellitus (n= 5). Twelve patients were treated with corticosteroids and six were treated with anti-TNF therapy. The pretreatment median hemoglobin level was 9.5 gr/dL (5.6- 12.6 gr/ dL) and after the treatment it was 11.8 gr/dL (7.4-14.1 gr/dL) (Table 2). Additionally, we found a statistically significant difference between the baseline biochemical iron metabolism parameters pre-and post IV iron treatment (Table 2). Thus, we corroborated that IV iron was an effective therapy in our patients.

Table 1. The principal diagnosis of the patients included in the study

Table 2. The baseline laboratory iron metabolism parameters pre-and post-intravenous iron treatment

MCH – mean cell hemoglobin;
MCHC – mean cell hemoglobin concentration;
RDW – red cell volume distribution width.

No patients had more than one bacteremic episode within the month prior to treatment. Twenty-four patients (12.9%) suffered from one infection episode after the IV iron treatment, and 162 patients (87.1%) did not have any infection episodes. The majority of these infections were from bacterial microorganisms (75%, n=18) followed by unknown etiologies (16.7% n=4) and viral episodes (8.3%, n=2). There were no fungal infections. The urinary tract was involved in 33.3% of the cases (n=8); 25% of the cases involved therespiratory system (n=6), which was similar to the unknown focus case percentage; and 16.7% of the cases involved the gastrointestinal system (n=4). The infectious agent was unknown in 63.5% of the cases (n=15). The pathogens responsible for these episodes were E coli (16.7%, n=4) followed by E faecalis, E faecium, Lysteria and Proteus mirabilis, which all occurred in 4.2% of the cases (n=1). No intracellular microorganisms or non-capsulated bacteria were found in our series. Additionally, no serious diseases and no mortality cases were reported three months after the treatments began.

The main characteristics of the patients with and without infection episodes are shown in Table 3. More patients with an infection episode had a comorbidity (diabetes or malignancy) and ongoing immunosuppressive therapy than the patients without infections. However, this was not statistically significant. Furthermore, when we analyzed the relationship between infections with other comorbidities, such as diabetes, cancer, transplantation or treatments such as steroids or anti-TNF we did not find any association.

Table 3. Comorbidity incidences in the infection or no infection groups

NS – Non-Significant

Discussion

Almost all life forms require iron because of its involvement in basic cellular processes. Free iron was shown to potentiate bacterial growth in vitro. [13] In fact, during infections, pathogens use various means to acquire iron from their hosts, whereas hosts attempt to withhold it from pathogens. [14, 15] Iron therefore represents a point of conflict between the host and the pathogen, and an altered iron balance associated with poor outcomes in several infectious diseases, including malaria, [7] tuberculosis, [16] and HIV-1 infection. [17] Furthermore, certain bacterial species, including E. Coli, Klebsiella spp., and Salmonella spp., use unbound iron in the blood to enhance their growth. These organisms release siderophores, which are iron chelators, into the blood. Once these siderophores are released, bacteria can compete with proteins, such as transferrin for unbound iron in the serum. [18, 19] Staphylococcus aureus and Haemophilus influenzae do not possess siderophore; however, they do have transferrin receptors, which allow these bacteria to use iron for growth. [18] Vibrio vulnificus cannot grow if there is no iron available, and their virulence depends on the ability to obtain iron combined with transferrin. Hepcidin, which is produced during innate immune responses to infections, reduces the iron availability in the serum by inhibiting ferroportin function in macrophages and enterocytes and potentially limits extracellular pathogen growth therein. [20] Intravenous iron may also impair immune function and increase infection susceptibility. [21] Gupta et al. [22] found that exposure of mononuclear cells to IV iron agents induced significant intracellular oxidative stress and shortened CD4+ T lymphocyte survival. High doses of IV iron agents impaired the phagocytic activity and microbial killing capability of polymorphonuclear leukocytes [23-25]. Furthermore, in a recent in vitro study, iron sucrose led to impaired phagocytic function and increased polymorphonuclear leukocyte apoptosis. [26] However, the current evidence in clinical practice cannot determine whether iron supplementation increases the risk of infection or worsens outcomes due to infection. [27, 28] There is increasing data to suggest that infective and adverse-event risks may be related to the intensity and frequency of IV iron dosing. [29-31] Brookhart et al. [32] studied iron dosing patterns in a retrospective cohort of 117.050 prevalent hemodialysis (HD) patients and found that administration of large boluses of IV iron for repleting iron deficiency was associated with increased infection-related hospitalization or death compared with smaller doses of IV iron maintenance therapy. The risk of infection-related hospitalization was increased further in patients who experienced infections within the past month. Similarly, the DOPPS study showed a trend towards an increase infection.related mortality in prevalent HD patients treated with > 300 mg of IV iron. [33] A recent meta-analysis of randomized controlled trials evaluating IV iron use (often administered as frequent boluses) in patients with varying infective risk profiles found IV iron to be associated with a 30% greater risk of infection compared with oral or no iron therapy. [34] Conversely, a prospective observational study of 985 patients failed to demonstrate a relationship between infection and serum ferritin or IV iron dosing. [35] In our study, large IV iron boluses were an effective treatment for anemia that was caused by different etiologies, because hemoglobin increased at 2 or 3 points at the end of the treatment and we found any relationship between IV iron administration and infection, which was similar to the previously published data. Furthermore, in our study, transferrin saturation increased to 23.5%, thereby leaving little to no unbound iron available for bacterial utilization, as shown in previous in vitro studies. [10] For example, in the K. pneumonia case, bacterial suppression occurred throughout its incubation until the transferrin saturation exceeded 60%, at which time bacterial growth occurred. [19] Another in vitro study showed that the inhibition of Staphylococcus epidermidis growth was lost once the transferrin saturation exceeded 80%. [18] Subsequent studies had ambiguous results that left the relationship somewhat unclear. [36, 37] In a retrospective observational cohort study of 23.000 adult patients on HD hospitalized for bacterial infection, Ishida et al. found no association between iron treatment and readmission for infection. [38] Feldman’s group, in a re-analysis of their HD cohort using multivariable analysis, showed no statistically significant association between any level of iron administration and mortality. [39] Moreover, a French multicenter prospective study regarding bacteremia risk factors in HD patients (EPIBACDIAL) did not find any correlation between parenteral iron or ferritin and bacteremia. [40] Furthermore, in the Anker study, quality of life and functional status improved in heart failure (a relatively high-risk group) without an increase in infections [41].

Our study had limitations due to its retrospective nature. However, of the patients who were analyzed, we found a 12.8% infections after the beginning of iron therapy. Notably, an important difference in our study compared with the previously published studies was that we did not find any association between IV iron treatment and intracellular pathogens.

In conclusion, based on our study, iron treatment is safe and it does not associate with the development of new infections. However, the infection relationship is not clear and many studies are treating to investigate the different mechanisms regarding this issue. It is important to verify this result with other studies to improve the care and future treatment of patients because iron treatment is frequently used worldside. This knowledge can improve anemia management and avoid side effects. Thus, large multi-centered randomized controlled trials designed to evaluate both the short- and long-term safety of different IV iron dosing regimens are still required to determine the optimal iron therapy.

Conflict of interests

No conflict of interest exists and all authors had full access to all the data used in the study and take full responsibility for the decision to submit the manuscript for publication.

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DOI: 10.31038/IMROJ.2017213

Abstract

Asthma is an important chronic disease affecting a lot of people worldwide. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This manuscript emphasizes on new generation monoclonal human (ized) antibodies in asthmatics and off-label use. The first developed biologic agent is the anti- immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma.

Introduction

Asthma is an important chronic disease affecting a lot of people worldwide [1]. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This special issue emphasizes on new generation monoclonal human (ized) antibodies in asthmatics [2-4].

The pathophysiological mechanisms underlying asthma, which is a heterogeneous disease, are characterized by interactive responses among various cell types and the hematopoietic cells of the adaptive and innate immune systems. Frequently is conventional therapy like inhaled steroids and beta-agonists sufficient for asthma symptoms. However, a little minority of the asthmatics is not controlled with conventional therapy. Therefore, are new treatment options essential for severe asthmatic patients [5].

Anti-IL-5 Molecules

Interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells play an important role in the pathogenesis of asthma. Monoclonal antibodies targeting these cytokines as treatment for severe asthma are expected to be beneficial [6]. Eosinophilic inflammation is an important event in the pathogenesis of asthma. IL-5 is a key cytokine that arranges eosinophil production, survival, maturation and recruitment of eosinophils to the inflammation [7]. Mepolizumab, reslizumab, and benralizumab are new developed monoclonal antibodies that target the cytokine IL-5. Mepolizumab and reslizumab have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with severe asthma with an eosinophilic phenotype [8,9]. Mepolizumab and reslizumab binds directly to IL-5 ligand. These molecules effectively decreased circulating and sputum eosinophil counts, but they failed to improve airway mucosal eosinophilia, acute exacerbation rates, lung function and symptom scores in several studies. These disappointing results may be affected from inappropriate selection of the patients. In order to overcome the probable mechanistic limitations of early anti-IL-5 agents, an anti-IL5R monoclonal antibody was developed and called as benralizumab. Benralizumab, previously known as MEDI-563, is a humanized recombinant IgG1-k isotype monoclonal antibody. It was constructed from the mouse anti-human IL-5Rα mAbs generated by mice immunized with recombinant human IL- 5Rα [10]. Clinical studies revealed that anti-interleukin 5 monoclonal therapies for asthma could be safe for slightly improving FEV1 (or FEV1% of predicted value), quality of life, and reducing exacerbations risk and blood and sputum eosinophils. However these drugs have no significant effect on PEF, and SABA rescue use. These may be a result of patient selection. Further trials are required to clarify the optimal antibody for different patients [7].

Anti-IL-4/IL-13 Molecules

Another investigated cytokine important in the inflammatory pathways in the pathogenesis of asthma is anti-IL-4. IL-4 is a pleiotropic cytokine secreted mainly by activated T cells. Mast cells, basophils, and eosinophils can also secret IL-4 [10,11]. IL-4 is important in inducing IgE isotype switching, T cell polarization into Th2 cells, and generation of IL-4, IL-5, and IL-13 by Th2 cells. IL-4Rα is expressed on CD4+ and CD8+ T cells, B cells, macrophages, lung epithelial cells, airway goblet cells, and smooth muscle cells [11]. There is a functional homogeniety between IL-4 and IL-13. IL-4 can activate a heterodimeric receptor complex consisting of the IL-4 receptor α- subunit (IL-4Rα) and a γC subunit. IL-13 can activate the IL-4Rα and the IL-13 receptor α1-subunit (IL-13Rα1) [5]. Both IL-4 and IL-13 can bind to heterodimeric combination of the α-subunit of the IL-13 receptor and the α-subunit of the IL-4 receptor. And this leads to signaling of both IL-4 and IL-13. Therefore, will blocking IL-4R α with an antibody of this receptor chain expected to block the effects of both IL-4 and IL-13 [6].

Pascolizumab and VAK694 are anti-IL-4 neutralizing monoclonal antibodies. Also, IL-4 receptor antagonist drugs like dupilumab, pitrakinra and AMG-317 have been discovered. Even a recombinant IL-4Rα that captures soluble IL-4 and prevents their binding to IL-4 receptors, has been developed. It is called altrakincept. However, further research on this drug was discontinued by its manufacturer, since the phase 3 clinical trial failed to confirm its earlier promising results. Since there is a high redundancy of IL-4 and IL-13 signaling, blocking of both IL-4 and IL-13 has been expected to be more efficient [11]. Dupilumab is a drug that inhibits signaling from IL- 4 and IL-13 concomitantly. It is a molecule that binds to the alpha subunit of the IL-4 receptor. Phase II trials for dupilumab showed that asthma exacerbations were decreased in patients using this drug [12,13]. Dupilumab also improved lung function. It reduced the inhaled corticosteroid dose in the patient group. There was also an associated reduction in fractional exhaled nitric oxide with reduced serum concentrations of Th2-associated inflammatory markers such as CCL17 (TARC), CCL26 (eotaxin-3), and IgE [6]. These results are promising and further clinical trials will us show us the long-term efficacy of dupilumab [11].

Another similar drug that targets IL-4 is pitrakinra. It is a recombinant human IL-4 variant that competitively inhibits IL-4Ra to interfere with the actions of both IL-4 and IL-13. Studies on this competitive antagonist called pitrakinra revealed that it leads to significant reduction in asthma exacerbations and improves asthma symptoms in patients with eosinophilia [14]. Pitrakinra also attenuated the late-phase asthmatic response to allergen challenge in patients with mild atopic asthma [6]. The other drug called AMG317 was evaluated in another phase II trial in approximately 300 patients with moderate to severe asthma. Weekly injections over 12 weeks were well tolerated but did not have significant effects on the Asthma Control Questionnaire score (ACQ score; the primary outcome) [14].

Interleukin 13 shares 30% homology with interleukin 4. IL-13 is secreted by Th2 cells, ILC2s, mast cells, basophils, and eosinophils. IL-13 has the potential to increase goblet-cell differentiation, and activation of fibroblasts. IL-13 production can induce an increase in bronchial hyperresponsiveness, and switching of B-cell antibody production towards IgE [6]. IL-13 is similar to IL-4 and uses the same signaling pathways. The high-affinity receptor of IL-13 is a heterodimer of IL-4Rα/IL- 13Rα1. IL-13Rα1 is present on eosinophils, B cells, monocytes, macrophages, smooth muscle cells, lung epithelial cells, airway goblet cells, and endothelial cells. Biologicals that target IL-13 are anti-IL-13 mAbs: anrukinzumab, dectrekumab, GSK679586, IMA-026, lebrikizumab, RPC-4046, and tralokinumab [11].

Patients with severe asthma often have elevated levels in sputum despite therapy with high dose inhaled or oral corticosteroids. Lebrikizumab is one of the many humanized monoclonal antibodies that have been developed to specifically bind to IL-13 and inhibit its function [14]. In a randomized, double-blind, placebo- controlled study were 219 asthma patients observed and evaluated whether the drug lebrikizumab could alter the course of asthma. Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab. This therapy needs futher evaluation before being utilized in clinics [15]. Another monoclonal antibody called tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, has been evaluated in adults with moderate to severe uncontrolled asthma despite controller therapies. Patients were randomly assigned to receive tralokinumab or placebo subcutaneously every 2 weeks for 13 weeks. Although it had an acceptable safety and tolerability, it did not reduce asthma exacerbations [16].

Antithymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine that may trigger allergic inflammation and, thus, play a role in allergic asthma [17]. It is an epithelial-derived cytokine and makes its effect through its receptor, TSLP-R, which is a heterodimeric receptor that consists of the IL-7 receptor alpha chain (IL-7Rα) and the TSLP receptor alpha chain 1 (TSLPRα). In hematopoietic cells, TSLP-R is mainly expressed in DCs, monocytes, B cells, T cells, NK cells, invariant natural killer T (iNKT) cells, eosinophils, basophils, and mast cells [11].

A human anti TSLP monoclonal immunoglobulin G2 lambda (AMG 157) that binds human TSLP and prevents receptor interaction was assessed in a trial. Randomly assigned 31 patients with mild allergic asthma received AMG 157 (700 mg) or placebo intravenously, once a month for three doses. The primary outcome, the maximum percentage decrease in the FEV during the late asthmatic response was 45.9 percent less in the AMG 157 group than the placebo group on day 84. AMG 157 reduced allergen induced bronchoconstriction and airway inflammation. No serious adverse effects were reported. Further studies on this drug are planned to clarify its use in clinical practice [17].

Anti-IL-9 Monoclonal Antibody

IL-9 is a Th2 cytokine and a T cell and mast cell growth factor. Anti-IL-9 antibody-treatment has been shown to protect from allergen-induced airway remodeling, with a concomitant reduction in mature mast cell numbers and activation. It can also decrease expression of the profibrotic mediators transforming growth factor (TGF)-b1, vascular endothelial growth factor (EGF), and fibroblast growth factor-2 (FGF-2) in the lung. The function of IL-9 in allergy has been investigated for its pleiotropic activities on cell types associated with allergic diseases including Th2 lymphocytes, mast cells, B cells, eosinophils, and airway epithelial cells. An anti-IL-9 monoclonal antibody (MEDI-528) has been studied in a clinical trial on 327 asthmatic subjects. Patients were randomized to receive placebo or one of three doses of MEDI-528 (dosage 30, 100, or 300 mg s.c. twice weekly for 4 weeks) in addition to their usual asthma medications. The addition of MEDI-528 to existing asthma controller medications did not improve ACQ-6 scores, asthma exacerbation rates, or FEV1 values. Further clinical trials are needed to explore this drug for altering the course of asthma. Thus, the potential clinical benefit of targeting IL-9 or its receptor in the treatment of asthma remains to be shown in further studies [5].

Anti-IL-2 antibody

Allergen exposure can stimulate IL-2 and its receptor expression (IL -2R) a chain (sCD25) in airways of patients with severe asthma. Daclizumab is a humanized monoclonal antibody that binds specifically to a subunit (CD25) of the high-affinity IL-2R, and inhibits IL-2 binding and its biological activity. Daclizumab can inhibit various T cell functions, including T cell proliferation and cytokine production. It has been investigated in a randomized controlled study. The drug has the potential to improve pulmonary function and asthma control in patients moderate to severe chronic asthma [18]. The risk of immunosuppression in clinical practice needs to be clarified.

Anti-GATA3-spesific DNAzyme

Approximately half of the asthmatic patients exhibit a Th2 type in response to allergen exposure. This Th2 endotype is characterized by a predominant activation of Th2 cells that produce cytokines such as interleukins 4, 5, and 13. The expression and production of all these Th2 cytokines have been shown to be controlled by the zinc finger transcription factor GATA3, which is essential for Th2-cell differentiation and activation. It is considered to be the master transcription factor of the Th2 pathway of immune activation. Therefore, could be interventions to disrupt this immune network, a synthetic DNA molecule (DNAzyme), that binds to GATA3 messenger RNA and cleaves it, a solution. This synthetic molecule called SB010 could significantly attenuate both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis after this drug showed an attenuation of Th2-regulated inflammatory responses [19].

Anti-IL-17 antibody

Although half of the asthma patients exhibit a Th2 type endotype, some remaining patients exhibit a Th17 driven endotype. This subpopulation is characterized with a Th17 driven inflammation. Th17 cells can contribute to airway hyperresponsiveness by recruiting both eosinophils and neutrophils. Therefore, has been IL-17 receptor blocking suggested to beneficial in asthma treatment [20]. Biologicals targeting IL-17 include an anti-IL-17A mAb: secukinumab and an anti-IL- 17 receptor mAb: brodalumab. Although the inhibition of IL-17 receptor A had no effect on subjects with asthma as a whole, a subgroup analysis showed an effect with uncertain significance. Further studies are needed to determine the role of secukinumab in asthma [11]. Brodalumab (AMG 827) is a human, anti–IL-17RA immunoglobulin G2 (IgG2) monoclonal antibody that binds with high affinity to human IL-17RA, blocking the biologic activity of IL- 17A, -17F, -17A/F heterodimer, and -17E (IL-25). Brodalumab can block IL-25 activity and IL-17A and IL-17F. In a randomized controlled study were 302 patients taking this drug evaluated and at the end of the study there was no evidence for an effect of brodalumab in these patients. Further studies may clarify the potential of this drug [20].

Anti TNF antibodies

In addition, human(ized) monoclonal antibodies (HMA) evaluated for the treatment of severe persistent asthma (SPA), but not approved after Phase II trial are as follows; Infliximab (Recombinant human–murine chimeric anti-TNFα monoclonal antibody Infliximab), etanercept (Soluble TNFα receptor fusion protein), and golimumab (Fully human TNFα-blocking antibody) [5]. The expression of TNF alfa is increased in asthma in association with airway neutrophilia. Berry and colleagues have demonstrated that the TNF-α axis is upregulated in patients with refractory asthma, as evidenced by the increased expression of membrane-bound TNF-α, TNF receptor 1, and TNF-α– converting enzyme by peripheral-blood monocytes [21]. Treatment with golimumab did not demonstrate a favorable risk-benefit profile in patients with severe persistent asthma [22]. A study with etanercept showed a small decrease in asthma exacerbations was observed in a randomized placebo controlled study [23]. In a case-series report was it told that in severe, uncontrolled, steroid-dependent asthma infliximab could reduce exacerbations and hospitalizations [24]. In some severe refractory asthma endotypes anti-TNFα therapy may have a role. However, it should be kept in mind that these agents have some safety concerns and should use carefully only in some severe refractory asthma endotypes [5].

ANTI-IgE

The first developed biologic agent is the anti-immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma [5].

The other human(ized) promising monoclonal antibody drug developed, but not approved yet is ligeluzimab. Ligeluzimab binds with very high affinity to the Cε3 domain of IgE. Ligeluzumab may provide longer supression of IgE. Trials with this biologic agent are ongoing [5].

Anti-ige: off-label use non-atopic asthma

The off-label use of omalizumab in patients with uncontrolled non-atopic asthma has resulted in a decrease in exacerbation rates and improvement in asthma symptom scores. In a study conducted in 2013, omalizumab was administered to 266 patients with severe allergic asthma and 29 patients with non-atopic severe asthma for two years, and the study found a decline in the exacerbation rate, increase in the quality of life, and significantly improved disease control in both groups [25-27]. In two studies which used omalizumab in a group of patients with non-atopic severe asthma, the authors observed downregulation of FcRI expression in the basophils and increased FEV1.

Nasal polyposis, allergic rhinitis, and allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis affects 7 to 9% of patients with cystic fibrosis (CF) and 1 to 2% of patients with asthma, posing a diagnostic challenge [28,29]. Cases series related to ABPA were first published in 2007. In a series of eight cases with cystic fibrosis and ABPA published by Tanou et al. [30] in 2014, the authors reported increased FEV1, improved respiratory symptoms, and reduced steroid consumption. In a series of six cases with CF diagnosed with ABPA published by Lehman et al. [31], the authors reported improved symptoms in patients receiving omalizumab, whereas the efficacy of the treatment was less pronounced in patients diagnosed with ABPA and long disease duration and in patients who developed progressive lung problems [31]. In a series of 14 patients with severe asthma and ABPA in 2015, Aydın et al. [32] showed that 11 patients achieved complete and three patients achieved partial response. The authors also reported an overall improvement in the pulmonary functions and respiratory symptoms with a statistically significant reduction in the use of oral corticosteroids (OCS) and number of disease episodes. Also, the patients with a total immunoglobulin E (IgE) level of <1,000 IU showed a better response to omalizumab, compared to those with a total IgE level of >1,000 IU. However, this finding was found to have a low-evidence level, considering the lack of large-scale, prospective case series and randomized and placebo- controlled studies.

Efficacy and safety of omalizumab were first evaluated in a randomized, double-blind, placebo-controlled study of 221 patients with seasonal allergic rhinitis in 2002 [33]. This study reported a significant symptomatic relief up to 48% in the combination treatment group (specific immunotherapy [SIT]+omalizumab), compared to SIT group alone. A randomized study in Japan reported a significant improvement in daily nasal and eye symptoms in patients with seasonal allergic rhinitis receiving omalizumab [34].

In 2007, a randomized placebo-controlled study of eight patients was the first to report reduced rates of postoperative polyp recurrence in patients with atopic asthma and nasal polyps (NP) [35]. In a study of 19 patients with severe asthma and NP in 2011, Vennera et al. [36] reported symptom reduction and disease stabilization with the use of omalizumab treatment. In addition, Tajiri et al. [37] evaluated omalizumab in patients with severe asthma and NP, and reported significant improvements in nasal symptoms, asthma control, and sinus tomography results. However, not all studies were able to show the beneficial effects of the treatment. In a randomized, double-blind, placebo-controlled study of patients with chronic rhinosinusitis receiving omalizumab, Pinto et al. [38] showed improvement in the Sino-Nasal Outcome Test (SNOT-20) scores at three, five, and six months, although there was no significant difference in the scores compared to the control group. The aforementioned study did not observe any changes in the quality of life, symptom scores, cellular inflammation, nasal passage, and olfactory test parameters.

Atopic Dermatitis And Food Allergy

In a series of three patients published in 2005, the authors reported no response after four months of treatment [39], while Lane et al. [40] published a series of three patients in the same study period and reported successful treatment outcomes of severe AD using omalizumab [40]. In addition, a pilot study of 21 patients published in 2009 found a statistically significant clinical improvement in all patients [41]. Another series of three patients published in 2011 reported significant improvement in the Eczema Area and Severity Index (EASI) and itching severity score in patients with severe AD unresponsive to conventional treatment and those with elevated IgE levels [42]. A study of 11 patients published in the same year reported reduced SCORing Atopic Dermatitis (SCORAD) scores, reduced symptoms, and significant improvement in the quality of life (3). The efficacy of omalizumab was also evaluated in 20 adults with severe AD in a prospective, 28-week, open-label study conducted by Hotze et al. [43] in 2014. The authors reported no response to treatment in seven patients harboring filaggrin gene mutation (FLG), while there was a significant improvement in the remaining eight patients. The authors also concluded that the patients with FLG gene mutation were prone to achieve lower response to omalizumab.

Furthermore, in food-related immunotherapy (IT) studies, omalizumab initiated before or received simultaneously with the treatment facilitated the development of tolerance. In a series of 11 patients with cow milk allergy scheduled for IT, 10 patients tolerated daily intake of 8 g cow milk after the initiation of omalizumab, nine weeks before IT, and combination with IT treatment, thereafter [44]. Another use of this treatment is to facilitate a rapid and safe transition to the maintenance phase in patients with food allergy receiving oral IT [45]. Another use of the treatment in food allergy is eosinophillic esophagitis developing in association with multiple food allergies. Also, in a study administered omalizumab to patients with eosinophillic esophagitis, the authors found reduced allergic symptoms and improved quality of life, although there was no change in endoscopic and histologic characteristics of the disease [46].

Food Allergy and Anaphylaxis

Anaphylaxis can occur as a result of exposure to various allergens such as food, drug, and venom; however, no triggering factor can be shown in some cases, of which the latter is known as idiopathic anaphylaxis. The patients with elevated baseline tryptase levels or those diagnosed with mastocytosis are expected to have higher rates of anaphylaxis with a more aggressive course of disease. In particular, patients with venom allergy on IT may experience some difficulties in switching to maintenance dose. Severe anaphylactic episodes can be observed in patients diagnosed with mastocytosis on IT due to venom allergy. In addition, IT combined with omalizumab has enabled a safe transition to the maintenance phase in this group of patients [47-49]. Addition of omalizumab to rush and ultra-rush venom IT protocols has increased the success of IT and enabled a safer transition to the maintenance phase. Another use of omalizumab is to prevent recurrent anaphylactic episodes in patients who are unable to be controlled with conventional therapies [50- 55]. There are case reports on the role of this treatment in preventing idiopathic anaphylactic episodes [56-58].

Several studies have reported asthma symptom control, improved quality of life, and development of tolerance to aspirin in two patients with the use of omalizumab in patients with aspirin-induced airway disease, nasal polyps, and severe asthma [59, 60]. Two patients with recurrent insulin allergy, despite the use of desensitization protocols, and one patient of carboplatin allergy during carboplatin therapy due to ovarian cancer successfully continued their treatment with the addition of omalizumab to the treatment [61-63].

In conclusion, although omalizumab has been approved for the treatment of severe allergic asthma and chronic idiopathic urticaria, it offers an off-label use as a final resort in many allergic diseases. Recent studies have shown that omalizumab is effective in treating bullous pemphigoid, Stevens-Johnson syndrome (SJS)/toxic
epidermal necrolysis (TEN, Type-III/IV reaction, such as graft versus host disease), Netherton syndrome, asthma and chronic obstructive pulmonary disease overlap syndrome (ACOS). Its effects on soluble inflammatory markers, such as sCD200, sTRAIL, hematopoietic cells, Th1/2 cytokines (CXCL8; IL-1β; IL-4; IL-5; IL17A), total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations were demonstrated in several studies [64-70].

Monoclonal antibodies are a candidate for use in several indications with the contribution of large-scale studies to the literature in the near future.

Declaration of Interest

All authors declare that they have no conflict of interest.

Acknowledgements

Prof.Dr. Tse Wen Chang, Prof.Dr.Saadet Gumuslu, Prof.Dr. Fatih Uz, Prof.Dr Arzu Mirici.

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DOI: 10.31038/IMROJ.2017212

Introduction

The autonomic nervous system (ANS) is an arm of the nervous system surrounded by the peripheral nervous system (PN) and the central nervous system (CNS). It is responsible for the regulation of involuntary bodily functions such as the beating of the heart to the way in which food is digested [1-4]. This system further separates into two division: the sympathetic nerves (SNs) and the parasympathetic nerves (PNs) with each carrying efferent (motor) signals to the heart and afferent responses to the brain [2,3]. In maintaining the body’s homeostasis, each nerve fibre triggers internal or external stimulus. Stimulations coming from the SNs releases epinephrine and norepinephrine prepare the body for stressful or emergency situations or what is best known as the fight or flight state [2]. SNs activities increase heart rate, cardiac output, contractility, conduction velocity and blood pressure during physical stimuli such as exercise [2]. SNs also makes the palm of the hand sweat, the pupils to dilate, and causes the hair on the body to stand on end [2].

In contrast, the PNs which originate from the brain stem and the sacral portion of the spinal cord releases acetylcholine to conserve energy during normal relaxed situations [2]. The efferent outflow termed the vagus nerve operates the parasympathetic to transmit nerves fibres to the lung, heart and other organs [2, 3,]. These nerves work to lower blood pressure (BP), to slow the heart rate (HR) down and to control digestive functions [2].

The SNs and PNs work in opposite direction of each other and as such the SNs enhance automaticity, while the PNs inhabit it [5]. A good demonstration of SNs and PNs operating in opposed action would be if the heart receives a neural stimulus from the parasympathetic branch; it would slow the heart down whereas sympathetic activities would speed up the heart. There is a wide consent suggesting that any changes between the systems play a role in pathological dysfunctions of the ANS [3-5]. For example, a cascade of adverse cardiac events takes place if parasympathetic vagal tone decreases [3, 5-6]. Hypertension-related diseases, coronary heart disease, heart failure and myocardial ischemia are various heart conditions caused by chronic SNs activation [5-8]. The shifts to a more sympathetic overdrive are a catastrophe for ANS impairment. As such any treatment whether by drug action or with exercise training that tilts the autonomic balance toward greater parasympathetic dominance and less sympathetic activity significantly improve prognosis [3].

Moreover, cardiovascular autonomic functions or dysfunctions are clinically evaluated by measuring resting heart rate (RHR), heart rate (HR), BP or heart rate recovery (HRR) [6]. Whether done directly or indirectly these autonomic parametres are good indicators in determining how the heart is working during conditions like exercise or stress [6,7,5,9]. In clinical practices, more specifically in cardiac rehabilitation (CR), several autonomic parametres are used in assessing patients ANS function and their physical capacity. Unfortunately, because of the difficulties and the lack of experience to perform some tests, and the time it takes to do the test, some methods are not applicable in CR setting [4].

In looking at different nerve simulations, clinical research studies found that ANS parametres were risk markers for cardiovascular diseases [5,7,9]. A decline in heart rate variability (HRV), for example, was associated with many cardiac conditions including sudden death [9]. Indeed clinical procedures like HRV in monitoring autonomic processes are necessary with patients. They are practical to check if the ANS is operating normally or to see if a disease or disorders are attacking the system. In this paper, we briefly look at the RPP and how the usefulness of this autonomic test is to CR. The RPP has been quoted in the literature, but it is now accepted as a reliable tool for making clinical decisions for exercise prescription.

Cardiac Rehabilitation and Exercise Testing (ET)

Cardiac rehabilitation is an outpatient health programme delivered by a multidisciplinary team of health professionals (i.e. physicians, nurses, exercise physiologist, dieticians) following cardiac incidents [10-13]. The plan typically provides a multifaceted offering of health services such as low to moderate exercise training, health education, risk factor modifications, counselling and social services [10-12]. The objective of CR is to enhance secondary prevention by lessening cardiac symptoms thereby reducing cardiac mortalities and morbidities for patients with cardiovascular disease [13]. Evidence demonstrate the efficacy of CR interventions where these schemes have improved patient’s quality of life (i.e. reduce depression, better risk profile, enhanced functional status) [12-14]. In one study a CR exercise-based programme was safe to improve cardiopulmonary function with patients who had preserved left ventricular ejection fraction (LVEF) and reduced LVEF [15]. In another research, the authors suggested following coronary artery bypass surgery exercise has the potential to better the long-term prognosis and lower the need for hospital care in cardiac patients [16]. CR is indicative in supporting cardiac autonomic functions to improve the long-term health and well-being of cardiac patients and their families.

Exercise prescription in CR is a determinant on patient’s ET results. Before the start of a CR programme, it is standard practice for all patients to undergo clinical assessments which include ET [11]. With a goal to boost patient’s clinical outcome, ET is done by evaluating left ventricular function (LVF) using an echocardiography or with a maximal exercise test limited by symptoms [11,17-20]. Before the beginning and ending of the programme, ET is the most critical testing component in CR. It provides plenty of information about patients’ functional capacity, their hemodynamic adaptation to maximal and submaximal levels of exercise HR and BP, their residual myocardial ischemia, and their cardiac arrhythmias which can be either induced or worsens with activity [20]. CR exercise testing also let us knows the amount needed to calculate patients training heart rate (THR) for the aerobic exercise [20].

The cardiopulmonary graded test or CPX is the gold standard and approved method used for CR exercise testing. Testing is conducted by treadmill walking, ergometre cycling, stepping, or performing a 12 minute timed walking test [11, 18-20]. During the CPX, patient’s peak oxygen uptake (VO2peak), their anaerobic threshold, their VE/VCO2 and O2 are observed as well as other parametres such as their maximal workload, and their resting and exercised BP and HR [20]. VO2peak is the most frequently analysed CPX parametre as it determines patients’ functional capacity, and it is the strongest prognostic for cardiovascular disease [20]. VO2peak provides information on exercise intensity with a percentage of 50% to 70% the most acceptable [18, 20]. Under the supervision of a healthcare professional patient’s workload is monitored at various exercise stage [18, 20]. They are asked about the perception of exercise intensity using the well-known Borg Rating of Perceived Exertion Scale (RPE) [11, 20]. Furthermore, it is advisable the patient completes each stages of exercise [11]. However, with their discretion, the physician or cardiologist could terminate the test at a particular heart rate or at the request of the patient [11].

Following the completion of ET patients HR, BP and their total VO2peak are recorded and analysed [20]. As a component of functional capacity, the VO2peak decides exercise prescription and is cited as an independent predictor of all-cause mortality in patients with cardiac conditions [11, 20]. After they have been discharged from CR, studies show patient’s functional capacity gets better [20]. The VO2peak test appears to be a valuable clinical assessment in the planning of patients’ management. If the test is not available to measure patients’ fitness capacity, the one metabolic equivalent (MET) formula is applied [11, 20]. The one METs is a very simple procedure to express the energy cost of physical activities as multiples of resting metabolic rate [11]. It is a measurement of the exertion intensity of physical activity, and it is defined by the amount of oxygen consumed while sitting quietly at rest and is equal to 3.5 ml O2 per kg body weight x min (i.e. 3.5 ml O2/kg/min) [11, 20]. For example, a physical activity requiring an 8-MET resting metabolic rate represents a VO2 of 28 ml • kg-1 • min-1. In calculating the absolute oxygen requirement of the activity with 8 MET the individual’s body weight is multiplied by the VO2 (kg-1 • min-1) (i.e. VO2 (kg-1 • min-1 =28 kg-1 • min-1 x 70 kg = 1.960 ml • min-1). A noted feature of the metabolic equivalent is that men and women do not produce the same values (i.e. METs= 14.7 – 0.11 x age for males and respectively 14.7 – 0.13 x age for females.) [20]. This gender difference in computation accounts for women’s having lower level of work capacity [11].

As mentioned earlier, patients’ exertion level in CR is estimated from the RPE scale. The scale ranges from 6 to 20, but the American Association of Cardiovascular and Pulmonary Rehabilitation (AACPR) suggest a RPE of 11 to 15 as a safe zone for patients [11]. An important characteristic of the RPE is that it works linearly with HR and with exercise intensity [11,21]. As such you can estimate the HR value of various levels of work intensity by adding a zero to each point on the PRE [21]. For instance, RPE of 6 becomes 60 and represents HR at rest, and 20 becomes 200, which may represent patients maximal HR [21]. Subsequently, you can use the RPP to know patients’ maximal HR and training workload. Case in point, if a patient develops some discomfort in the chest (i.e. angina pectoris) at a given level of exercise intensity, for safety the CR health professional should advise the patient to workout at a lower intensity. In this way, it would help to keep his training HR below the threshold where he may experience physical symptoms. The RPP is complementary to the RPE while having the ability to support safe CR exercise prescription for cardiac patients who might experience mild chest pain while they are exercising.

Rate Pressure Product (RPP)

To determine the energy requirement and establish the amount of stress put on the heart during exercise, cardiac specialist or exercise physiologists use the RPP. It is an observation of myocardial oxygen consumption (MVO2) [22-26] representing the internal myocardial workload when the heart beats while the external myocardial work is a reflection of different stages of exercise. [27]. Expressed as the product of systolic blood pressure (SBP) and resting heart rate, you can calculate the RPP by multiplying the SBP by the RHR and dividing by 100 (i.e. RPP = SBP x HR/100) [21-27]. PNs and SNs mediate both HR and SBP with SBP only affected by SN [25]. What’s more, depending on the individual physical or health condition RPP score may vary. Fornitano and de Godoy suggested RPP above 30,000 mmHg bpm are good values to predict the absence of obstructive coronary artery disease in patients with positive ET [27].

Heart Rate and Blood Pressure on Exercise Training

The heart needs sufficient amount of oxygen to work properly, and if there is not enough supply, it will cause the heart to weaken (e.g. heart failure) [22]. In this case, the RRP is important in providing information on patients’ myocardial oxygen consumption [20]. Blood pressure and HR is a determinant of physical fitness since they both increase during exercise, but not at the same pace [20, 24, 25]. In subjects with BP between 110 to 120 systolic and 60-80 diastolic whereas resting heart rate (RHR) is 65 to 70 beats per minute (bpm) is considered normal [26]. Under these conditions, the heart does not need to work as hard because the oxygen demand is less [26]. Conversely, in patients with BP over 140/90 mm Hg and an RHR of 85 bpm or higher the heart works harder as it requires more oxygen [26].

Typically, an increase in HR during exercise is a sign that more blood and oxygen is travelling to the working muscles, while elevated BP indicates more blood gets pumped to the heart [24, 26]. As noted, increased BP and HR do not occur at the same time. Thus, a rise in HR triggers blood vessels to widen which in turn helps to keep BP under control [24]. This situation is why healthy people can recover much faster from exercise as compared to someone with a medical condition [20, 22]. The quick recovery is also a sign that there is more parasympathetic vagal tone and less sympathetic activity, which also accounts for the reduction in HR [22].

Extensive clinical and rehabilitation studies on the impact of RPP noted its efficacy as a reliable index to assess patients’ with cardiovascular conditions or related complications on myocardial oxygen consumption during their exercise. Coelho and colleague identified positive changes in MVO2 values following training in patients with ischemic heart disease [28]. Keyhani and co-authors investigated the effects of an eight-week CR aerobic exercise programme on BP, HR, and RPP in patients with congestive heart failure (CHF) found their cardiac functional capacity improved as well as their autonomic function [29]. Still, Adams et al. compared peak RPP values with various modes of aerobic exercise after CR training discovered treadmill walking to associate with a higher score while resistance training produced a much lower number [21].

Looking at the RPP and autonomic responses of Tai Chi practitioners and non-practitioners at rest and using two different stressors: hand gripping and standing Figueroa and colleagues saw improved autonomic function (i.e. parasympathetic tone) with the Tai Chi group [27]. The Tai Chi practitioners’ sympathetic outflow and RPP were also significantly lower at rest suggesting they were better efficient in myocardial oxygen use during resting and pathological stress [27]. The positive outcomes are a testament that the RPP is a reliable tool and an acceptable approach in observing patient’s cardiac autonomic exercise responses that favour greater parasympathetic tone.
The magnitude and the time BP and HR changes after the cessation of exercise are not without discrepancies [28]. When compared to pre-exercise during the first hour of recovery, Somers et al. [30] found lower BP levels, whilst Pescatello et al. [30] saw a significant fall that was up to 12 hours following exercise. Equally, post-exercise HR was reported to enhance, cause no change or decrease [30]. These observations give us a hint that different exercise intensity, duration, and mode significantly influence BP and HR responses following training. Forjaz et al. [31] study recognised that exercise training at a lower intensity, does not only generate a small increase in RPP during exercise, but it also decreases post-exercise rate at rest. By doing so, this reduces myocardial oxygen consumption and lower cardiovascular risks after exercise. In regards to exercise at moderate or high intensity, RPP appears to be greater during training but it decreases below baseline following the recovery period [31]. As cited RPP varies with exercise and there is evident it has clinical implications in providing exercise prescription with those experiencing medical conditions [30].

Conclusion

In addition to standardised CR exercise tests, the RPP supplements with other ET. This autonomic measurement is efficient as gives clues and evaluates patient’s physical or cardiac functional capacity, exercise tolerance and oxygen demand during CR exercise testing and training. Importantly, its utilisation offers support to CR health professionals in selecting the right exercise intensity or training method for those patients whom may show cardiac risk.

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DOI: 10.31038/IMROJ.2017211

Abstract

A cross-sectional survey was conducted to appraise basic food safety practises by street or open-air market vendors about the township of Goroka in late 2014. Study subjects were randomly selected over a period of two months. Of the one hundred and twenty food vendors observed in the survey, most had unconventional methods of handling food or allowed consumers to pick up food with bare hands if they choose. Use of gloves was hardly observed. Only thirty-two percent handled cooked food with thongs or fork which was apparent at barbeque sites. Twenty-one percent of the subjects in the survey did not provide proper food wrappers. Water use was limited to fresh fruit sale but obviously lacking in all others. Practically all cooked-food vendors did not use covers on food containers consequently increasing the risk of environmental or fly contamination. This survey clearly demonstrates that street food vendors either possess limited knowledge of food safety and hygiene, or just improvise to earn a living. The activity is widespread and unregulated. However, such practise can easily set the stage for an outbreak of food-borne infection. Vulnerable consumers could be at particular risk and the practise could also help maintain and spread existing infections.

Key Words

Street food safety, sanitation, street food, vending and Papua New Guinea

Background

Easy access to clean water and proper sanitation relates to better health as much they are essential preconditions for promoting basic food safety [1-4]. Maintenance of hand hygiene through washing and use of gloves can lessen the level of contamination thereby ensuring food safety [4-7]. Contamination can occur during handling, processing or storage but can be minimised if appropriate safety measures are observed and those involved have a clear knowledge of basic food safety practises [8-10]. Some studies have found that the level of food contamination is associated with hygiene awareness and the attitudes of people involved in the business [11-13]. Contamination risk is nevertheless heightened if there is a notable gap in basic food safety knowledge and practise. [1, 3]. In Papua New Guinea, most diarrhoeal infections originate from contaminated food or water subsequent to poor sanitation or inaccessibility to clean water [14]. Cooked food sale in the open environment in the highlands is common. It is an informal sector practised by locals including the unemployed. Food such as cooked vegetables, meat, rice or floor is often prepared at homes and brought to the vending site. The food is usually packed in large bowls, or cooking pots and transported to vending site as opposed to static food warmers used in restaurants or other established outlets where a certain level of food safety is assured. Ready-to-eat food sale in open- air-market or street could be possibly compromised if there is a lax in food safety during preparation or storage for the duration of vending [15, 16]. On the other hand, vendors may not be obliged to adhere to basic food safety measures as the activity is not regulated [17, 18]. This survey aims to identify key gaps in basic food safety practise with respect to handling, protection from environmental contamination and easy access to clean water.

Materials and Methods

A cross-sectional survey was conducted in late 2014. It involved observing and recording the sale of ready-to-eat food, particularly cooked food by open-air-market or street vendor about the township of Goroka in the eastern highlands of Papua New Guinea. Sample size determination was not necessary as target subjects were limited and variable at the different sites visited. Data was obtained by observing key questions in a brief questionnaire without having to making verbal contact or interviewing subjects involved in the cooked-food sale. The anonymous approach by this this survey guaranteed confidential use of data. Questions were rather basic with the assumption that most of the vendors would possess basic concepts of hygiene and food safety despite having no formal training on food safety. Different sites were visited including the main market in town where such activities are competitive and frequent. Each questionnaire was completed through up-close examination of food containers, covers used on containers, serving utensils such as thongs, food wrapping and use of gloves. Observations were done on different occasions but it is possible some subjects may have appeared more than once in the survey as cooked food sale is common in the area. Necessary details of the vending events were captured in the questionnaire and analysed using Ms Excel.

Figure 1. Observed food safety measures

Results

Following the survey, majority of the street and open-air-market vendors failed to maintain basic food safety. Categories of food observed in the survey were basically local, cooked food (Table 1). The hundred and twenty (n=120) vendors observed apparently demonstrated a low level of hygiene or food safety practise. Glove use (0%) was not observed through the entire duration of the survey although most vendors applied irregular measures of food handling (32%). It is probable that such food were prepared in similar manner and transported. Food wrapping (21%) appeared to be improvised in some instances where old newspapers were used. On the other hand, local consumers had a tendency to pick up food with bare hand or simply choose to eat despite the obvious. Hygiene about the vending sites was questionable as running water or basic sanitation infrastructure was non-existent with periodic waste management. It is a widely known concept that hand hygiene is maintained through washing particularly during food preparation. However, water use was only observed in peeled, fresh-fruit sale (31%). Virtually all food containers or boxes had covers stripped off (16%) purposely to allow visibility of food to prospective consumers. This practise exposed food to environmental or fly contamination. In contrast to barbeques, most other cooked food sale did not maintain heat so evidently food went cold after a while. The practise appeared to be regular throughout the duration of the survey with similar method of food preparation. All measures undertaken by vendors to ensure food safety were documented (Figure 1).

Table 1. Types of ready-to-eat food sold at streets or open-air-markets

Discussion

Sale and consumption of ready-to-eat food in streets or open-air-markets in the highlands of Papua New Guinea is common amongst locals simply because they are within a consumer’s means and convenient than restaurants or established fast-food outlets [16]. However, open-markets are makeshift and mobile, therefore lack the necessary structure to protect and maintain food safety [17]. Poor regulation of the practise and overall insanitary conditions of the environment and vending sites raises serious issues of both health and food safety [18]. The apparent lack of water and sanitation infrastructure at designated markets should be also be a concern for overall public health safety [13, 18]. It was evident that individuals involved in this trade were semi-educated and possessed limited knowledge of basic food safety or would have had partial exposure to such information including personal hygiene [15]. The activity cannot be banned as it is an income-generating for many locals and unemployed town residents. The consistent demand for these easily accessible and cheap foods will certainly encourage and sustain the trade. This survey emphasizes the need to develop street-food safety by initiating awareness and education on basic food safety and raises the need to formulate appropriate codes of practise in accordance with the Hazard Analysis Critical Control Point (HACCP) guidelines [19, 20]. Moreover, public health authorities could consider developing policies aimed at training and registering or licensing street-food vending.

Conclusion

This survey clearly demonstrates that there is a poor level of food safety observance by vendors and consumer alike. In a region where diarrhoeal diseases are endemic and sanitation is deplorable, such vending practise has the potential to trigger enteric disease outbreaks [14, 21]. However, these vending practises are likely to continue unhindered unless relevant authorities step up. Contamination of food is likely and can easily set the stage for an outbreak of food-borne infection or associated diarrhoeal illness particularly amongst the vulnerable populations [13]. In addition, the practise could also help maintain and spread existing infections. Further study is required to determine the extent of microbial contamination on food samples and hands of food handlers in the open-air-market vending business. A major limitation to this study is the obvious lack of a structured interview to establish individual knowledge of food safety and use of raw materials for food preparation.

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