Risk factors associated with the severity of pneumonia in a cohort of hospitalized children in a rural setting

INTRODUCTION

Pneumonia is a major contributor to childhood mortality and morbidity in developing countries.^[1,2] The past decade has seen important declines in pneumonia-related mortality and to a lesser extent pneumonia-related incidence.^[1] From 2005 to 2015, the total number of under 5 deaths globally due to pneumonia decreased by 36.9% (95% uncertainty interval [UI] 31.6–42.0) from an estimated 1.11 million (95% UI 1.03–1.20 million) to 0.703 million (95% UI 0.651–0.763 million).^[1] However, the incidence of pneumonia only declined from 0.18 episodes per child year (95% UI 0.61–0.20) in 2005 to 0.15 episodes per child year (95% UI 0.13–0.17) in 2015.^[1] In South Africa, pneumonia remains the leading single cause of death in children under 5 years of age accounting for 8.6% of child deaths.^[3]

There are many well-recognized risk factors for pneumonia including adverse birth outcomes (being born preterm, low birth weight, or small for gestational age), young age, incomplete vaccination status, and malnutrition. Patients with severe pneumonia may have multiple risk factors acting in synergy resulting in more severe disease manifestation. The global and national trend toward the reduced burden of disease caused by pneumonia in children under 5 years highlights the important progress made in preventative strategies. Notable interventions include decreased indoor and ambient air pollution, improved childhood nutrition, greater coverage of childhood vaccines, progress made in HIV treatment, and case management of pneumonia.^[1,2]

Evidence relating to household risk factors for pneumonia remains sparse in the South African context. Combustion of biomass fuels resulting in household air pollution (HAP), overcrowding, and maternal smoking is associated with an increased risk of pneumonia.^[4-9] HAP is estimated to cause a high burden of morbidity and mortality globally, and of importance is the associated risk of lower respiratory tract infections (LRTIs).^[4] A systematic review and meta-analysis demonstrated that passive smoking in the family home is associated with a risk of LRTI in infants.^[10] South African studies including the Drakenstein Child Health Study and a case-control study conducted at Chris Hani Baragwanath Academic Hospital observed that tobacco smoke exposure was an independent risk factor for pneumonia.^[7,8] Overcrowding is also a well-described risk factor for pneumonia.^[5-7] These household risk factors, independently or interdependently, may play a significant role in the development of pneumonia. Whether they are associated with the severity of pneumonia in this population remains unknown. South African primary health care has focused on immunizations, nutrition, and case management of HIV and TB. However, there is limited understanding of household environmental factors and related interventions. Understanding the role of environmental risk factors associated with severe pneumonia may provide insight into areas that require immediate intervention in resource-limited settings.

The aim of this study was to determine factors associated with the severity of pneumonia in hospitalized children in a rural setting, with a primary focus on household environmental factors and secondarily child and caregiver factors.

MATERIALS AND METHODS

We conducted an unmatched case-control study of children aged 0–59 months admitted with severe pneumonia (cases) compared to non-severe pneumonia (controls). The study took place at WPH (Worcester, South Africa) between January 1^st and December 31^st, 2019. WPH is a regional public hospital, which provides specialist support to district hospitals and is located in the Breede Valley, approximately 110 km from Cape Town.

Eligible participants were children aged 0–59 months admitted with respiratory symptoms suggestive of clinical pneumonia. The pediatric ward and intensive care unit (ICU) admissions registers were reviewed during weekdays for eligible candidates. We conducted structured interviews with consenting primary caregivers, in a language of the caregivers’ choice, detailing information related to the child, primary caregiver, and household risk factors. Medical information related to pneumonia, anthropometric data, and HIV status were collected from the admission notes and supplemented by a review of the Road to Health Booklet. Laboratory investigations and/ or chest X-rays were performed at the discretion of the treating clinical team and no additional study-specific investigations were requested.

The primary outcome of pneumonia was classified according to the WHO clinical definition of pneumonia as severe or non-severe following a review of the completed admission notes.^[11] Severe pneumonia was defined as cough or difficulty breathing and age-appropriate threshold for tachypnea or chest indrawing AND any one of the following features: hypoxemia (oxygen saturation of <92% in room air), respiratory support (i.e. high flow oxygen, CPAP, ventilatory support, and ICU admission), OR any integrated management of childhood illnesses general danger signs. Non-severe pneumonia was defined as cough or difficulty breathing AND age appropriate threshold for tachypnea or chest indrawing in the absence of hypoxia and any danger signs AND not requiring respiratory support. Although non-severe pneumonia in isolation did not warrant admission, children with comorbidities and those requiring supplemental oxygen but not hypoxic were admitted for observation and therapy. The diagnosis of bronchiolitis was based on clinical features manifesting as cough and wheeze.^[12,13] The diagnosis of bronchopneumonia was based on clinical and radiological evidence of pneumonia characterized by suppurative inflammation localized in patches around bronchi which may or may not be localized to a single lobe of the lung.^[14] Asthma was diagnosed clinically as recurrent and reversible episodes of bronchial obstruction manifesting in shortness of breath and wheeze that responded to bronchodilators.^[12,13] The discharge diagnosis was based on cumulative information during the admission, including clinical presentation, inpatient records, and any additional investigations.

Clinical records and laboratory results were used to determine HIV status. The WHO classification of breastfeeding was used to categorize patients as not breastfed, partially breastfed, predominantly breastfed, or exclusively breastfed. Nutritional status was classified using sex-appropriate WHO child growth charts as appropriate weight-for-height, underweight-for-age, stunted, or wasted (moderate or severe).^[15]

Indoor smoke exposure refers to biomass fuel used to generate energy for the purposes of cooking, heating, and lighting. Indoor tobacco smoke exposure refers to any household member that smoked including caregivers. Household crowding was defined as more than two people per household room.^[16] This excluded bathrooms but included kitchen and living room areas.

Data were entered into a primary data collection tool developed in Research Electronic Data Capture (REDCap).^[17] Basic descriptive statistics were conducted using IBM SPSS Statistics (Version 27). The association between severe pneumonia and adverse household environmental factors – tobacco smoke exposure, indoor smoke exposure, and overcrowding –was evaluated using the parametric Chi-square test if assumptions were met or the non-parametric Fisher’s Exact test when assumptions were not met. Unadjusted odds ratios (ORs) of the primary and secondary exposures were calculated comparing children with severe and non-severe pneumonia using univariable logistic regression. We additionally conducted multivariable logistic regression to estimate adjusted ORs including a priori identified confounders of age, sex, preterm birth, breastfeeding, nutrition status, HIV infection and exposure, participant comorbidities, immunization status, caregiver age and level of education, and additional factors associated with an outcome at P < 0.1. Using different multivariate regression models, we assessed the association of the adverse household environmental factors (indoor tobacco smoke exposure, overcrowding, and indoor biomass fuel exposure) individually and in combination.

Ethics approval was obtained from the Health Research Ethics Committee of Stellenbosch University and the Provincial Government of the Western Cape Health Impact Assessment.

RESULTS

Between January 1^st and December 31^st, 2019, we enrolled 305 children, of which 134 (43.9%) were categorized as severe pneumonia and 171 (56.1%) as non-severe pneumonia [Figure 1].

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Figure 1:

Flow diagram of participant inclusion.

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DISCUSSION

Pneumonia remains an important public health burden and determining factors that may mitigate severe disease have beneficial implications in resource limited settings. These factors may help inform interventions and policy decisions in an already constrained health-care system.

This case–control study compared risk factors of cases with severe pneumonia to unmatched controls with non-severe pneumonia admitted to a regional secondary level rural hospital. We compared infant, caregiver, and household risk factors and found a predominantly homogenous group of participants with few significant variations between cases with severe pneumonia and controls with non-severe pneumonia. These similarities were noted in baseline characteristics including a similar education level with most caregivers having achieved some secondary education or matriculated and residing in formal dwellings. Established risk factors for pneumonia were also similar between groups, with the majority of children being less than 7 months of age at the time of admission, almost a quarter born preterm, 87% appropriately immunized and just over half having been exclusively breastfed for 6 months. The distinguishing feature among these groups related to children with severe pneumonia having greater odds of living in a household with a pit latrine toilet compared to children with non-severe pneumonia.

As expected, a large proportion of participants were infants in the 1^st year of their life. Severe pneumonia and non-severe pneumonia in the early months of life reflect the vulnerability of this young age group which is consistent with studies in low-to-middle income countries.^[8,19,20] Our study, however, did not demonstrate group differences related to age, indicating that young age, though a known risk factor for pneumonia, was not a factor associated with the severity of pneumonia in this study. More than a quarter of participants were preterm with the majority of participants appropriate for gestational age. Prematurity is associated with immature immune function, reduced production of pro-inflammatory cytokines, and reduced passive immunity conferred by transplacental maternal antibodies.^[21-23] Despite prematurity being a known risk factor for pneumonia,^[23,24] it was not associated with greater odds of severe disease when comparing severe pneumonia with non-severe pneumonia. This was demonstrated in both late and early preterm births. These findings differ from that of the Drankenstein Child Study which demonstrated that age <2 months and preterm birth were significantly associated with serious outcomes.^[24] This discrepancy may be due to the difference in study design and the population sampling used.

According to the WHO definition of pneumonia, all children with evidence of severe acute malnutrition and features of respiratory tract infection are considered to have severe pneumonia; thus, we could not evaluate severe acute malnutrition as an independent risk factor for severe pneumonia. Despite evidence to support the importance of malnutrition as a risk factor for pneumonia,^[25,26] there was no observable association with the severity of disease. This observation may be artifactual due to assigning severely malnourished children automatically to the severe pneumonia group and essentially excluding them from analysis.

Prevention of childhood communicable diseases through immunization plays an important role in reducing pneumonia mortality, morbidity, and burden of disease.^[27,28] This important preventative strategy, however, was not associated with severe pneumonia in this study with similar and fairly good immunization coverage reported in the severe pneumonia and non-severe pneumonia groups. In addition, routine immunizations do not cover the most common causes of pneumonia such as respiratory syncytial virus, parainfluenza virus, and adenovirus.^[20] Although determining the infective agent was not part of this study, the young study cohort would have been more vulnerable to these viruses.

While HIV-infection was low (1.3%), HIV exposure without infection was fairly prevalent (17.3%) in this study. Our study did not demonstrate an association with HIV infection or HIV exposure without infection and severe pneumonia. This subgroup may have been too small to demonstrate smaller differences between groups, requiring a greater sample. Alternatively, this may reflect the strength of the PMTCT program in this community and possible immune reconstitution in patients living with HIV reducing the risk of severe disease.

Tobacco smoke exposure is a well described risk factor for pneumonia in studies conducted in South Africa and Cameroon.^[7,8,29] The Drakenstein Child Health Study, a birth cohort study conducted outside of Cape Town, demonstrated in regression models that maternal smoking was an independent risk factor for pneumonia. The Drakenstein Study included ambulatory and hospitalized LRTIs and was conducted at two separate clinics. This study used WHO criteria to define pneumonia similar to our study, but the clinic setting and ambulatory LRTI were a noted difference.^[30] A case–control study conducted at Chris Hani Baragwanath Academic Hospital also observed that a primary caregiver who smoked was a risk factor for pneumonia (aOR: 5.15, 95% CI: 2.94– 9.03).^[7] This study, however, did not use the WHO criteria for pneumonia and was conducted in a tertiary hospital. The study conducted in Cameroon assessed pneumonia risk factors using a cross-sectional study at a secondary hospital. This study included both ambulatory and hospitalized acute respiratory tract infections and found that passive smoking was associated with acute respiratory tract infections. There were notable differences in study design and sample selection in all three studies. These differences in study design and sample selection may represent different populations with different risk factors and disease severity compared to the cohort admitted to WPH and included in our study.

Our study reflected less smoking in caregivers in the severe pneumonia group than the non-severe pneumonia group. This unexpected observation may have been due to reverse causality bias implicated in the study design and behavior change following hospital admission of participants. Caregivers may have felt guilty about volunteering accurate information related to smoking habits and underestimated the exact amount of cigarettes smoked. This may have been more pronounced in the severe pneumonia group causing behavioral change and reporting socially desirable information rather than that increased tobacco smoke exposure may be protective.

Our study did not demonstrate that household smoke exposure was associated with the severity of pneumonia. Although the burning of coal for household cooking, heating, or light demonstrated increased odds of developing severe pneumonia, it was not statistically significant however, the study may have been under-powered to identify this difference.

Overcrowding, although an established risk factor for pneumonia, was not associated with the severity of pneumonia. In contrast, our study demonstrated that having a greater number of household members was associated with reduced odds of developing severe disease. This may be due to larger households being able to provide more childhood monitoring, stimulation, caregiving, education, and financial support in this generally socioeconomically vulnerable population.

In relation to the primary study objective, no association was demonstrated in univariable or multivariable analysis between adverse household environmental factors and severe pneumonia. Severe pneumonia was only associated with greater odds in households that reported use of pit latrine toilets. This association may represent the most indigent of this community and their increased risk of developing severe disease. Further analysis of socioeconomic disparities may be helpful in assigning risk to other adverse household environmental factors and the detection of protective factors. Investigations into the accessibility to clean water, sanitation, and waste disposal or the lack thereof would provide important information about the socioeconomic circumstances that this community experiences and the risk of disease. It is also interesting to note that a greater association of severe disease was demonstrated in those that reported use of pit latrine toilet as opposed to those having no toilet facility. This may be related to methods of waste disposal, hygiene, and sanitation around pit latrine facilities.

Caregivers that reported no toilet facilities may also have had access to alternative amenities such as their neighbor’s lavatory or rented facilities. Further inquiry into these circumstances are needed to shed more light on the matter.

In an attempt to help inform interventions and policy decisions to mitigate pneumonia severity, we continue to advocate for primary health interventions. Primary interventions such as childhood immunizations, maternal education relating to smoking and smoke exposure, exclusive breastfeeding, appropriate education on nutrition, and compliance with vertical HIV transmission prevention guidelines remain important strategies to reduce community respiratory disease burden. Parallel strategies to improve living conditions and alleviate poverty through appropriate housing, access to sustainable energy, clean water, sanitation, and appropriate sewerage disposal are of equal importance and complement interventions.

CONCLUSION

This cohort provides a comparison of risk factors in children admitted with severe pneumonia and non-severe pneumonia in a rural setting in South Africa. We compared child, caregiver, and household risk factors and found a predominantly homogenous group of participants with few significant variations. These similarities were noted in both baseline characteristics and risk factors. The distinguishing feature among these groups related to children with severe pneumonia having greater odds of living in a household with a pit latrine toilet compared to children with non-severe pneumonia. This may represent the socioeconomic differences of this cohort and the risk associated with developing severe pneumonia in the most marginalized and vulnerable part of the population.