Etiology and patterns of acute respiratory infections in low- and middle-income countries: implications for vaccination strategies and environmental interventions Restricted; Files Only

Hamid, Sarah (Spring 2022)

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Acute respiratory infections (ARI) are a leading cause of mortality, especially in low- and middle-income countries (LMIC). Respiratory syncytial virus (RSV) and Streptococcus pneumoniae are recognized as leading causes of lower respiratory infection morbidity and mortality. Household air pollution (HAP) from cooking with solid fuels is the leading environmental risk factor. Quantifying the etiologic role of respiratory pathogens, describing their patterns, and identifying effective interventions targeting the environmental drivers of disease are essential to reduce respiratory disease burden. The overarching goal of this dissertation is to shed light on the etiology and patterns of ARI in LMIC in order to better inform vaccine strategies and environmental interventions.

In Aim 1, we characterized RSV seasonality in Guatemala. We found substantial variability in the timing of seasonal epidemics such that two differential patterns of RSV seasonality were identified: an early season starting in June-July and a late season starting in October-November. This variability suggests that age-based vaccination would be more effective than seasonal vaccination.

In Aim 2, we assessed whether prenatal HAP exposure is associated with respiratory illness in two-year-old children using data from a liquified petroleum gas stove intervention during gestation and the first year of life in Guatemala, India, and Rwanda. In an intent-to-treat analysis, we did not find an effect of the intervention on illness with a cough in two-year-old children. Similarly, we did not find evidence of an association between HAP and illness with cough in an exposure-response analysis.

In Aim 3, we estimated the fraction of hospitalized ARI attributable to S. pneumoniae, and assessed whether a semi-quantitative measure of bacterial load (PCR quantification cycle [Cq] values) could improve understanding of the etiologic role of S. pneumoniae in hospitalized ARI in adults in six LMIC. Population attributable fraction estimates that incorporated Cq values were higher than those that relied on qualitative PCR. The proportion of hospitalized ARI attributed to S. pneumoniae varied across countries, ranging from 0.1% to 18.5%.

These findings further our understanding of the etiology, patterns, and environmental risk factors of ARI in low-resource settings, and can inform vaccine strategies, environmental interventions, and healthcare management practices.

Table of Contents

Chapter 1. Introduction 1

Specific aims 4

Chapter 2. Background and Literature review 7

Case definitions 7

Lower respiratory tract infection (LRI) 7

Pneumonia 7

Acute respiratory infection (ARI) 7

Severe acute respiratory infection (SARI) 8

Disease burden 8

Etiologic agents 9

Streptococcus pneumoniae 11

Associations of Pathogen Load with Disease 13

Respiratory Syncytial Virus 16

Household air pollution 21

Chapter 3. Respiratory syncytial virus seasonality in Guatemala, 2008-2018 27

Abstract 27

Introduction 28

Methods 30

Results 35

Discussion 37

Chapter 4. Effects of a 500-day liquefied petroleum gas stove intervention during gestation and infancy on respiratory illness in children at 24 months of age. 52

Introduction 52

Methods 56

Results 60

Discussion 63

Chapter 5. Real-Time PCR quantification cycle values to estimate the population attributable fraction of Streptococcus pneumoniae in severe acute respiratory infections in adults in six countries: a prospective case-control study. 79

Abstract 79

Introduction 80

Methods 82

Results 86

Discussion 88

Chapter 6. Summary and conclusions 107

Summary of findings 107

Limitations 109

Future directions 112

References 114

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