Burden and mortality of pneumonia

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Introduction

Pneumonia is a major cause of morbidity and mortality in children worldwide and causes 18% of all deaths in children less than 5 years of age (Black, Cousens et al. 2010). Respiratory viruses traditionally associated with acute respiratory tract infection include influenza (INF) A and B; respiratory syncytial virus (RSV); parainfluenza virus (PIV) types 1, 2 and 3; adenovirus (AdV); enterovirus (EV); human metapneumovirus (hMPV) and rhinovirus (RV) (Brittain-Long, Nord et al. 2008, Tiveljung-Lindel, Rotzen-Ostlund et al. 2009).
While a few studies have determined the frequency of respiratory viruses in patients with acute lower respiratory tract illness in Africa, (Joosting, Harwin et al. 1979, Kristensen, Thiel et al. 2004, Madhi, Ludewick et al. 2007, Smuts, Workman et al. 2011) these studies have mainly been limited to single sites and a limited number of viruses, and little has been reported on viral co-infections Comparative studies have shown that the detection of respiratory viruses using real- time reverse transcriptase polymerase chain reaction (rRT-PCR) assays is substantially more sensitive than using conventional methods such as viral culture and immunofluorescence assays (IFA) (Hendrickson 2004, Paranhos-Baccala, Komuruan-Pradel et al. 2008, Lassauniere, Kresfelder et al. 2010). Furthermore, compared to conventional PCR and other real-time methods, multiplex rRT-PCR has a significant advantage as it permits simultaneous amplification of several viruses in a single reaction(Paranhos-Baccala, Komuruan-Pradel et al. 2008, Lassauniere, Kresfelder et al. 2010, Venter, Lassauniere et al. 2011). This facilitates cost-effective diagnosis, enabling the detection of multiple viruses in a single clinical specimen. In order to best understand the full burden of acute respiratory infection in South Africa, it is important to conduct surveillance and measure the burden of mild, outpatient disease as well as more severe, inpatient disease. By comparing the prevalence of these respiratory viruses detected in patients with influenza-like illness (ILI) and severe acute respiratory illness (SARI) to control patients the contribution of these respiratory viruses to SARI maybe better understood.

Pneumonia

Burden and mortality of pneumonia Previous estimates from the 1970’s to early 1990’s attributed up to a third of deaths in children aged less than 5 years were due to or associated with respiratory infection (Cockburn and Assaad 1973, Bulla and Hitze 1978, Leowski 1986, Garenne, Ronsmans et al. 1992). An increased focus on childhood mortality arising from the Millennium Declaration and the Millennium Development Goal (MDG) 4, which deals with the reduction of the mortality rate in children less than 5 years old with two-thirds by 2015. This focus made [16]monitoring the interventions to control these deaths crucial if these goals are going to be reached (Figure 1.1) (Rudan, Boschi-Pinto et al. 2008).
Several meta-analysis studies have since reported on childhood mortality in general and for specific syndromes like pneumonia and diarrhea (Rudan, Boschi-Pinto et al. 2008, Black, Cousens et al. 2010, Nair, Nokes et al. 2010, Nair, Brooks et al. 2011, Walker, Rudan et al. 2013). Rajaratnam et al.,2010 (Rajaratnam, Marcus et al. 2010) reported on the decrease in worldwide mortality in children less than 5 years of age from 11.9 million in 1990 to 7.7 million in 2010, however there was still a substantial amount of deaths occurring in the low-income countries: 33% in South Asia and 49% occur in sub-Saharan Africa, with less than 1% of deaths occurring in high-income countries. In their analysis which included data from 187 countries showed the number of deaths in children younger than 5 years dropped from 16 million in 1970 to 7·7 million in 2010. (Rajaratnam, Marcus et al. 2010). The set MDG 4 target for decrease in mortality in children younger than 5 years is 4.4% per year[16]. Taking into account the set target of 4.4% the 35% decline in childhood mortality reported in developing countries calculated to a yearly rate of 2.2%, which is lower that the MDG 4 target but still represents substantial progress across countries and economic status (Figure 1.2).
Incidence of clinical pneumonia In 2004 Rudan et al (Rudan, Tomaskovic et al. 2004) published one of the first global estimates of clinical pneumonia in children from developing countries. In the meta analysis from 28 different studies published since 1961 The median incidence estimated from those studies was 0.28 episodes per child-year. This equates to an annual incidence of 150.7 million new cases of childhood pneumonia, 11-20 million (7-13%) of which are hospitalized. Together with large population-based studies published from Europe and USA (McConnochie, Hall et al. 1988, Jokinen, Heiskanen et al. 1993, Weigl, Bader et al. 2003) which reported that the incidence of community-acquired pneumonia among children less than five years old is approximately 0.026 episodes per child-year, still suggests that 95% of all episodes of clinical pneumonia in young children worldwide occur in developing countries. A major public health to be considered is the distribution of the estimated 156 million new episodes by region and country to enable the role out of realistic preventative interventions and case management at community and facility levels which would include vaccination and antibiotic availability. Rudan et al., 2008

Table of Contents :

• Ethics
• Acknowledgements
• Summary
• Publications and Communications
• Table of Contents
• List of Abbreviations
• Table of Figures
• Table of Tables
• Chapter
  • Literature Review
  • 1.1 Introduction
  • 1.2 Pneumonia
    • 1.2.1 Burden and mortality of pneumonia
    • 1.2.2 Incidence of clinical pneumonia
    • 1.2.3 Childhood pneumonia
    • 1.2.4 Diagnosis of respiratory viruses
  • 1.3 Respiratory Syncytial Virus
    • 1.3.1 Classification
    • 1.3.2 Epidemiology
  • 1.4 Rhinovirus
    • 1.4.1 Classification
    • 1.4.2 Epidemiology
  • 1.5 Innate Immune Response
    • 1.5.1 RSV
    • 1.5.2 Rhinovirus
    • 1.5.3 Host factors
  • 2. Aim and objectives
  • 2.1 Aim
  • 2.2 Secondary objectives
• Chapter
  • Development and application of a 10-plex real-time polymerase chain reaction assay
  • to identify the common respiratory viruses in patients hospitalised with Severe Acute
  • Respiratory Illness—South Africa,
  • 2.1 Introduction
  • 2.2 Materials and Methods
    • 2.2.1 Setting
    • 2.2.2 Case Definition
    • 2.2.3 Validation and Optimization of Real-Time rRT-PCR Multiplex
    • 2.2.4 Nucleic acid extraction
    • 2.2.5 Primer and Probe multiplexing
    • 2.2.6 Real-Time RT-PCR
    • 2.2.7 Statistical Analysis
  • 2.3 Results
    • 2.3.1 Validation and Optimization of the Real-Time RT-PCR (rRT-PCR)
    • 2.3.2 Study group demographics
    • 2.3.3 Application of the rRT-PCR for screening of surveillance specimens
  • from patients with SARI
    • 2.3.4 Respiratory viral co-infections
    • 2.3.5 Seasonality
  • 2.4 Discussion
• Chapter
  • Investigation of the disease association of respiratory virus infection among patients
  • with severe acute respiratory illness and influenza-like illness in South Africa,
  • 3.1 Introduction
  • 3.2 Materials and Methods
    • 3.2.1 Study design and population
    • 3.2.2 Respiratory Virus detection
    • 3.2.3 Statistical Analysis
  • 3.3 Results
  • 3.3.1 Characteristics of the Study Population and Detection of Respiratory
  • Viruses
  • 3.3.2 Attributable fraction of respiratory virus infection to mild or severe illness
  • 3.4 Discussion
• Chapter
  • Genetic Diversity and Molecular Epidemiology of Human Rhinoviruses in South
  • Africa
  • 4.1 Introduction
  • 4.2 Materials and Methods
    • 4.2.1 Study design and population
    • 4.2.2 Sample Selection of Two Groups for Molecular Characterization
    • 4.2.3 Laboratory testing
    • 4.2.4 Statistical Analysis
  • 4.3 Results
  • 4.3.1 Phylogenetic comparison of rhinovirus strains identified in
  • and 2012-2013 cohorts
  • 4.3.2 Epidemiology of rhinovirus infection and factors associated with
  • rhinovirus type in 2009-2010 cohort
  • 4.3.3 Association of rhinovirus infection and rhinovirus-type with respiratory
  • disease severity in 2012-2013 cohort
  • 4.4 Discussion
• Chapter
  • Positive evolution and molecular epidemiology of subtype A and B Respiratory
  • Syncytial Virus G-protein genotypes from 1997-2013 in South Africa
  • 5.1 Introduction
  • 5.2 Materials and Methods
    • 5.2.1 Study design
    • 5.2.2 Sample Selection for Screening and Molecular Characterization
    • 5.2.3 Detection of Respiratory Viruses
    • 5.2.4 Full RSV G-protein gene amplification
    • 5.2.5 Subgrouping:
    • 5.2.6 Nucleotide sequencing
    • 5.2.7 Phylogenetic analysis
    • 5.2.6 Nucleotide and amino acid sequence analysis
    • 5.2.8 Evolutionary rate and most recent common ancestor (MRCA)
    • 5.2.9 Selective pressure analysis
    • 5.2.10 Statistical analysis
    • 5.2.11 Nucleotide sequence accession numbers
  • 5.3 Results
  • 5.3.1 Detection of respiratory viruses and characteristics of RSV-positive
  • patients identified in the SARI surveillance program during
  • 5.3.2 Evolution of RSV subgroups
  • 5.3.3 Phylogenetic comparison of strains identified in 2006-2013 relative to
  • earlier periods
  • 5.3.4 Disease association of RSV-A and B
  • 5.4 Discussion
• Chapter
  • Naturally occurring Respiratory Syncytial Virus A and B Glycoprotein ecto-domain
  • deletion mutants- association with severe acute respiratory illness in HIV-infected
  • South Africans
  • 6.1 Introduction
  • 6.2 Materials and Methods
    • 6.2.1 Study design and population
    • 6.2.2 Sample Selection for Screening and Molecular Characterization
    • 6.2.3 RSV detection
    • 6.2.4 Screening for G-protein deletion mutants:
    • 6.2.5 RSV genome sequencing
    • 6.2.6 Phylogenetic analysis of full genome sequences
    • 6.2.7 Accession Numbers for reference sequences
    • 6.2.8 Inflammatory cytokines and chemokines
  • 6.3 Results
    • 6.3.1 Initial identification of South African deletion mutants
    • 6.3.2 Full genome analysis of South African G-protein deletion mutant strains

• Chapter
  • T-helper 1 and 2 cytokine responses associated with severe acute respiratory illness
  • in immune compromised infants infected with rhinovirus vs. respiratory syncytial
  • virus
  • 7.1 Introduction
  • 7.2 Materials and Methods
    • 7.2.1 Study design and population
    • 7.2.2 Laboratory testing
    • 7.2.3 Sample Selection for Cytokine screening
    • 7.2.4 Cytokine assay
    • 7.2.5 Statistical analysis
  • 7.3 Results
    • 7.3.1 Characteristics of study children
    • 7.3.2 Cytokine levels
  • 7.4 Discussion
• Chapter
  • Concluding remarks

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