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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 2-7

Serum nonenzymatic anti-oxidants in Nigerian children with severe pneumonia: Association with complications and hospital outcomes


Department of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife, Nigeria

Date of Submission20-Jul-2020
Date of Decision23-Aug-2020
Date of Acceptance27-Aug-2020
Date of Web Publication08-Dec-2020

Correspondence Address:
Bankole Peter Kuti
Department of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_7_20

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  Abstract 


Background: Tissue damaging effects of free radicals generated during the acute inflammation processes of childhood pneumonia may be ameliorated by antioxidants. This study aimed to determine the serum non-enzymatic antioxidants {Total Phenols, Carotenoids, Flavoids, Ascorbic acid, Tocopherols and Total Antioxidant Contents (TAC)} of Nigerian children with or without severe pneumonia (SP) and relate these to the presence of parapneumonic effusions (PPE) and length of hospitalisation (LOH). Methods: Consecutive children two months to 14 years admitted with severe pneumonia and their age and sex matched controls were recruited over a 12-month period at a Nigerian Health facility. Serum antioxidants were assayed using chromatography method and related to PPE and LOH. Results: The majority (86.1%) of the 144 children (72 each with SP and controls) were under-fives and eight (11.1%) of SP group had PPE. Median (IQR) LOH was 5.0 (4.0 – 7.0) days and 45 (62.5%) had prolonged (≥5 days) hospital stay with 3 (4.2%) mortality. Serum Tocopherols, 10.1 (4.7) vs. 13.2 (7.6) µg/dl; total flavoids 1.0 (0.6) vs. 1.3 (0.8) µg/dl and TAC 6.1 (4.4-8.9) vs. 7.4 (5.0 – 13.3) ng/dl were significantly lower in children with SP (p < 0.05). Serum antioxidants levels were not related to the PPE, however children with prolonged LOH had lower TAC (p<0.05), which also correlated negatively with LOH (r =- 0.418; p < 0.001) Conclusion: Lower serum antioxidants observed in children with severe pneumonia may connote increased demand or increased predisposition to the infection. Antioxidant supplementation may aid recovery of Nigerian children with SP.

Keywords: Anti-oxidants, childhood pneumonia, length of hospitalization, oxidative stress


How to cite this article:
Kuti BP, Oyelami OA. Serum nonenzymatic anti-oxidants in Nigerian children with severe pneumonia: Association with complications and hospital outcomes. Pediatr Respirol Crit Care Med 2020;4:2-7

How to cite this URL:
Kuti BP, Oyelami OA. Serum nonenzymatic anti-oxidants in Nigerian children with severe pneumonia: Association with complications and hospital outcomes. Pediatr Respirol Crit Care Med [serial online] 2020 [cited 2021 Jan 16];4:2-7. Available from: https://www.prccm.org/text.asp?2020/4/1/2/302706




  Introduction Top


Pneumonia causes more ill-health and deaths in children than malaria, HIV/AIDS and tuberculosis put together.[1] These pneumonia-related deaths in children are particularly more common in low- and middle-income countries (LMICs).[1] Community-acquired pneumonia (CAP) in children accounts for about 15% of under-five mortality, which translates to over 800,000 childhood deaths per year[2] Nigeria bears the global lion share of childhood deaths from CAP with over 162,000 annual childhood deaths from pneumonia reported in Nigeria in 2018.[2]

Childhood CAP is often acquired through inhalation of pathogenic microbes or less commonly through haematogenous spread of microbes to the lungs.[3] Acute inflammation of the lung parenchyma is then initiated through cytokines, chemokines and other inflammatory mediators.[3],[4] There is also chemoattraction of inflammatory cells to the site and attempt to phagocytose and destroy the offending microorganisms - a process that involves respiratory burst and generation of reactive nitrogenous species (RNS) and reactive oxidative species (ROS).[3],[4]

Oxidative stress from the generated free radicals requires the action of endogenous anti-oxidants to limit the cell damage effects of these oxidants. These endogenous anti-oxidants include enzymatic anti-oxidants such as superoxide dismutase, glutathione peroxidase, glutathione reductases and catalases.[5] The nonenzymatic anti-oxidants like phenols, carotenoids, Flavonoids, Vitamin C (ascorbic acids) and E (Tocopherols) are needed to ameliorate the inflammatory and cellular damage effects of oxidative stresses generated by immune cells.[5],[6] While the enzymatic anti-oxidants act by converting oxidised metabolic products to hydrogen peroxide (H2O2) and water using cofactors such as iron, zinc, copper and manganese, nonenzymatic anti-oxidants intercept and terminate free radical chain reactions.[5],[6] All these actions convert harmful cytopathic free radicals to harmless metabolites.[6] Total anti-oxidant capacity (TAC), which is a measure of the summation of nonenzymatic anti-oxidant activities in the serum[7] have been reported to influence the severity of illness in children with sepsis and acute respiratory tract infections.[8],[9] The serum levels of anti-oxidants in children with CAP may, therefore, influence disease severity and outcome.

Nonenzymatic anti-oxidants are freely available in fruits and vegetables such as carrots, citrus fruits, lettuce, green leafy vegetables and tomatoes.[10] Nonetheless, many children in LMICs where the burden of childhood pneumonia is highest are deficient in many of these anti-oxidants as childhood undernutrition and micronutrient deficiencies are very common.[11] This may contribute to their increased susceptibility to pneumonia and other infections and probably their tendency to succumb to these infections. This study, therefore, aimed to compare the serum nonenzymatic anti-oxidants (total phenols, carotenoids, flavoids, ascorbic acids, tocopherols and TAC) of Nigerian children admitted with severe CAP and that of their age- and sex-matched apparently healthy controls and relate these anti-oxidants to pneumonia incidence, presence of PPE and length of hospitalisation (LOH).


  Methods Top


Study design and location

This hospital-based cross-sectional study design was carried out over a 12-month period (January to December 2019) at the Wesley Guild Hospital Ilesa, which is one of the tertiary units of the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria. Ilesa (Latitude 7°35’N and longitude 4°51’E) is located in the tropical rain forest region of southwest Nigeria.[12] The hospital offers primary, secondary and tertiary health-care services to the catchment population in Osun and neighbouring states in Southwest Nigeria.

Sample size estimation

The sample size was estimated using open Epi software®.[13] Based on the study of Cemek et al.,[14] the mean difference of serum ascorbic acid between children with CAP and controls was taken as 0.19 mg/dl and standard deviations from the mean for the two groups as 0.3 and 0.2 mg/dl respectively. At a 5% significance (alpha) level, 80% study power and 95% confidence interval and the ratio of cases to control being 1. The calculated sample size was 144 i.e., 72 children with CAP and 72 controls.

Study participants

These were children admitted with severe pneumonia between the ages of 2 months to 14 years and age- and sex-matched apparently healthy children. The controls were consecutively recruited from the daily child welfare clinic of the hospital after parental consent were obtained.

Study procedure

Definition of terms

Severe pneumonia was defined using the WHO criteria as age-specific tachypnoea (respiratory rate >50 breaths/min for children between 2 to <12 months; >40 breaths/min for those one to 5 years and >30 for those children >5–14 years); lower chest wall in-drawing; convulsions; central cyanosis; lethargy or altered sensorium and inability to feed or drink were classified as very severe pneumonia.[15] Parapneumonic effusion (PPE) was defined as the presence of pleural fluid collection on chest radiographs and/or with free-flowing fluid aspiration on percutaneous pleural tap.[16]

Children whose parents or caregivers did not give consent to participate in the study were excluded. Those with chronic cough (>2 weeks); acute or recurrent wheezing; and hospital-acquired pneumonia were also excluded.

Information obtained from the study participants and/or their parents included sociodemographic characteristics, housing, breastfeeding and immunisation history. Others included the use of biomass and other unclean fuel for cooking, lighting and heating. The children were classified into various nutrition categories based on the comparison of their weights and heights for age with the WHO growth reference standard for under-fives[17] and school-age children.[18] Socioeconomic class of the study participant was assigned using a validated tool[19] and overcrowding was defined as having three or more persons sharing the same standard room with the study participants.[20] The children were managed based on standard protocol and outcomes of hospital stay recorded.

Serum anti-oxidants and total antioxidant capacity assay

These were assayed by high-performance liquid chromatography (HPLC) methods using an automated 616/6265 transducer pump (Waters Incorporate, California, U.S.A) following standard protocol. The analysis was performed at the Analytical Services Laboratories of the International Institute of Tropical Agriculture, Ibadan, Nigeria. The summation of the individual HPLC peaks for total carotenoids, flavonoids, phenols and anti-oxidant vitamins defined the TAC. The background quality control check was done against Trolox®. Duplication of the blood sample was also done as quality control with the mean of the two results used as the estimated value. The inter-assay coefficient of variations (CVs) for TAC was ≤4.8%.

Ethical approval

This study was approved by the Ethics and Research Committee of the OAUTHC, Ile-Ife, Nigeria, with approval number ERC/2014/08/04. Written informed consent and assent (for children >6 years) were obtained from the caregivers and study participants, respectively.

Data analysis

This was done using SPSS for Windows software version 17.0 (SPSS Inc., Chicago 2008). Continuous variables such as serum anti-oxidants, TAC, and age were tested for normality using Kolmogorov–Smirnov statistics and summarised using mean (standard deviation) or median (interquartile range) for Gaussian and non-Gaussian distributed variables. Differences between continuous variables were ascertained with Student’s t-test or Mann–Whitney-U test as appropriate. The relationship between serum anti-oxidants, TAC and LOH were determined using Pearson or Spearman Rho correlations as appropriate. Age range, sex, socio-economic class categories and pneumonia severity were summarised using percentages and proportions, and the difference determined using Chi-squared or Fischer’s exact test. The effect size was estimated using mean difference and the level of significance at 95% confidence interval (CI) was taken as P < 0.05.


  Results Top


Characteristics of the study participants

A total of 144 (72 each for severe pneumonia and control) children were recruited. The median (IQR) age was 2.0 (0.8–3.5) years. There were 94 (65.3%) male children and the majority (80.6%) of the study participants were from middle and low SES. The sample population was enriched with children with appropriate immunisation status (84.0%), normal nutritional state (78.5%), but the use of clean fuel (30.6%) was less frequent. [Table 1] highlights the characteristics of the study participants. No significant difference in the age, gender and Socio-economic classification of the children with severe pneumonia and controls. However living in crowded homes, inappropriate immunisation and undernutrition were significantly more common in the severe pneumonia group [Table 1].
Table 1: Characteristics of the study participants

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Specific pneumonia complications

[Figure 1] highlights the complications observed among children with severe pneumonia. Heart failure (30.7%), parapneumonic effusions (12.5%) including empyema thoracic (6.9%) and serous pleural effusions (5.6%) were the most common complications. Two children had more than one complication.
Figure 1: Complications of severe pneumonia

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Outcome of hospitalisation

The median length of hospital stay was 5.0 (4.0–7.0) days, which ranged from 1 to 22 days. Forty-five (62.6%) had prolonged hospital stay (≥5 full days), sixty-nine (95.8%) were discharged home, while there were three (4.2%) cases of mortality.

Serum anti-oxidant profile of the study participants

[Table 2] highlights the selected serum anti-oxidant profile in children with severe pneumonia and controls. Serum total flavonoids, phenols, tocopherols and TAC were significantly lower in children with severe pneumonia than their age- and sex-matched controls (P < 0.05).
Table 2: Serum anti-oxidants of the study participants

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No significant association between serum antioxidants and the presence of parapneumonic effusions [Table 3] and other complications (not shown).
Table 3: Serum anti-oxidants as related to the presence of parapneumonic effusions

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Serum anti-oxidants and length of hospitalisation

The relationships between serum anti-oxidants and the presence and absence of prolonged hospital stay are highlighted in [Table 4], while the correlations between the anti-oxidants and length of hospital stay in [Table 5]. Only TAC was significantly associated with the prolonged hospital stay. Similarly, there was a significant negative correlation between serum TAC and LOH.
Table 4: Serum antioxidants as related to pronged hospitalisation

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Table 5: Correlation between serum anti-oxidants length of hospitalisation

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  Discussion Top


This study highlights significantly lower serum nonenzymatic anti-oxidants (Flavonoids, Phenols and Vitamin E and TAC) in a group of Nigerian children with severe pneumonia compared to controls. These anti-oxidants were not associated with disease severity; however, lower serum TAC was associated with the prolonged hospital stay. Major pneumonia-related risk factors (crowded homes, undernutrition, lack of immunisation and exclusive breastfeeding) were also highlighted and were modifiable. The discussion will address the relationship between these anti-oxidants and pneumonia incidence, severity and LOH. The significant lower serum anti-oxidants observed in the children with severe pneumonia compared to controls in this study was similarly reported by Cemek et al.[14] in Turkey and Bhoite et al.[21] as well as Vaidyal and Bulakh[22] in India. Lower serum anti-oxidants may predispose these children to having severe pneumonia as it reduces their ability to get rid of infectious agents.[5] Nonenzymatic anti-oxidants prevent lipid peroxidation and subsequent damage to the cell membrane of immune cells.[5],[6] Vitamin E is an anti-oxidant vitamin which had been shown to prevent the process of lipid peroxidation by trapping peroxyl radicals.[5],[6] The inability to limit the tissue-damaging effects of ROS and other free radicals generated by immune cells leads to the generation of more free radicals and perpetuation of the vicious cycle.[5],[6] Furthermore, children with infection may have more needs for anti-oxidants as they may have utilised the available serum anti-oxidants leading to relatively lower levels compared to controls. This cause-effect relationship may explain the lower serum anti-oxidants observed in the children with severe pneumonia compared to the controls.

The presence of parapneumonic effusions among the children with SP was not significantly related to serum anti-oxidants levels. There is a paucity of studies relating pneumonia complications and parapneumonic effusions with serum nonenzymatic anti-oxidants. However, Narsimha et al.[23] in a study of 90 adults in India reported significantly higher serum levels of oxidative markers (Malondialdehyde and lactate dehydrogenase) in adults with exudative pleural effusions, including parapneumonic effusions than those with transudative pleural effusions. Increased markers of oxidative stress will invariably increase the demands for anti-oxidants. Nonetheless, the roles of oxidants/anti-oxidants in pneumonia-related complications and lung injuries have been described as complex.[24] Anti-oxidants include a wide variety of enzymatic and nonenzymatic substances, including uric acids whose roles in lung pathology and defenses are still being investigated.[13],[25],[26] In addition, anti-oxidants may sometimes exhibit pro-oxidant properties, and pro-oxidants may not always be harmful.[6],[24],[25] Further studies to investigate the complex interactions between pro- and anti-oxidants in lung health and disease, including childhood severe pneumonia and its complications, will be worthwhile.

Serum TAC in our cohort of children with severe pneumonia was significantly lower in those with prolonged length of hospital stay. Implying serum anti-oxidants lower the period of hospitalisation as negative correlation was observed in this study. These support the findings of Wahed et al.[27] in India, where supplementation of children with anti-oxidant vitamins and micronutrients led to faster resolution of clinical signs of pneumonia and reduced LOH. Anti-oxidants prevent lung injuries by neutralising free radicals including ROS and RNS released by immune cells during the process of inflammations and preventing lipid peroxidation, thereby assisting in halting the vicious cycle of inflammation, free-radical generation, cellular damage and further acute inflammation. This explains the significant association of TAC with reduced hospitalisation in this study. However, a randomised controlled trial to determine the effects of anti-oxidants vitamin E and C as an adjunct therapy in the management of children with CAP reported no beneficial effects in terms of pneumonia outcome and LOH.[28] More studies on the roles of anti-oxidants in childhood pneumonia related morbidity and outcomes is hereby advocated.

Worthy of note from this study is that undernutrition, inappropriate immunisation and overcrowding were found to predispose to CAP among the recruited children. These were major risk factors to childhood pneumonia[2] and had also been reported by other workers in LMICs.[29],[30] Undernourished children have been reported to have increased markers of oxidative stress and reduced anti-oxidants.[10] This not only predisposes them to infections, it also increases their propensity to succumb to infectious diseases. Inappropriate immunisation and living in overcrowded homes are intrinsically linked to poverty and underdevelopment, which also manifests as poor access to health and childhood undernutrition.[31] Reducing childhood undernutrition as well as the standard of living and health inequalities among the underprivileged in LMICs, will assist in tackling the burden of childhood pneumonia.

Our study has many strengths, which include the assaying of the selected serum nonenzymatic anti-oxidants using quality assured HPLC methods in children with severe pneumonia in an LMIC where the burden of childhood pneumonia is very high. Furthermore, our sample size was adequate and pneumonia mimics such as bronchiolitis and other wheezing disorders were excluded making our cohort of pneumonia cases very homogeneous. We, however, recognise few limitations of this study, which include our inability to define the aetiologies pneumonia in our sample population and we did not study enzymatic anti-oxidants in this report. Furthermore, recruiting malnourished children without pneumonia as controls was difficult as most malnourished children usually have one symptom or another and often do not qualify as apparently healthy children. Nonetheless, this study will add to the few available reports about the roles of nonenzymatic anti-oxidants in childhood pneumonia incidence, complications and outcomes in LMICs.


  Conclusion Top


Modifiable factors such as crowded homes, inappropriate immunisation and undernutrition predispose Nigerian children to severe pneumonia. These children had significantly lower serum total flavonoids, phenols, tocopherols and TAC than controls. These anti-oxidants were however not associated with the presence of parapneumonic effusions and other complications. TAC nonetheless was associated with a prolonged hospital stay in the children with severe pneumonia. Appropriate housing and immunisation as well as adequate childhood nutrition, including anti-oxidant supplementation may reduce the burden of severe pneumonia in Nigerian children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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