Thesis (M.D.)--Boston University

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A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg 2017. / Introduction: Human rhinovirus (HRV) is the most prevalent virus detected in children with respiratory symptoms; however, its aetiological role during disease episodes remains unclear as detection of HRV is also ubiquitous among asymptomatic children. We evaluated the clinical epidemiology of HRV-associated disease among children hospitalised with severe and very severe pneumonia together with community control children living in Africa and Southeast Asia. In addition, we explored the associations between the molecular subtyping and nasopharyngeal viral loads of the HRV species and their ability to cause viraemia as potential markers for HRV disease. Methods: Using a case-control study conducted in seven countries, we compared the clinical characteristics of children (1-59 months of age) hospitalised with HRV-associated pneumonia between August 2011 - January 2014 and age-frequency matched controls. Nasopharyngeal swabs from the cases and controls were tested for HRV, together with 27 other respiratory pathogens, with quantitative real-time PCR assays. The 5’ NCR region of the HRV positive samples were sequenced to determine the species/strains of HRV and phylogenetic analysis was performed. Additionally, the blood samples from a limited number of cases (n=210) and controls (n=212) were tested for the presence of HRV viraemia and the 5’ NCR sequence of positive blood samples were further characterised. Results: Overall, HRV detection was 1.45-fold (aOR 95% CI: 1.29-1.62) higher among children hospitalised with pneumonia (24%) compared to controls (21%, P<0.005); including being 2.08-fold (28% vs 18%, aOR 95% CI: 1.75-2.47) more associated with case status among children 12-59 months of age. The HRV-associated cases were younger (13.1 months) than controls with HRV infection (15.4 months, P=0.001) and more likely to be malnourished (30% vs. 12%, P<0.001) and HIV-1 exposed (10% vs. 8%, P=0.046). HRV nasopharyngeal viral load was significantly higher among cases compared to controls (3.7 vs. 3.5 log10 copies/mL, P<0.001). Also, HRV viraemia was 7.02-fold (aOR 95% CI 1.70-28.94) more prevalent among cases (7%) compared to controls (2%, P=0.007). Moreover, HRV nasopharyngeal viral loads ≥4 log10 copies/mL differentiated between viraemia positive and negative cases. There was, however, no difference in the molecular subtyping of the HRV species prevalence among cases (HRV-A:48%; HRV-B:7%; HRV-C:45%) and controls (HRV-A:45%; HRV-B:10%; HRV-C:45%, P=0.496); as well as no evidence of seasonal or temporal clustering of the HRV species over time. Among cases, HRV detection was less likely to be associated with presence of radiographically confirmed pneumonia (40% vs 46%, P=0.001) or hospital stay >3 days (52% vs 61%, P=0.001). It was, however, positively associated with older age (13.1 months vs. 11.3 months, P<0.001) and presence of wheeze (46% vs. 31%, P<0.001) compared to the HRV uninfected cases. HRV was the sole virus detected in the 53% of cases and generally there were no differences in severity or clinical presentation among cases with HRV mono-infections compared to those with HRV-mixed infections. The HRV mono-infections, however, were associated with a 2.83-fold (aOR 95% CI: 1.44-5.53) higher case fatality ratio than cases with HRV and other viral mixed infections (10% vs. 5%, P=0.002). The HRV-associated case fatalities were more likely to have markers of bacterial co-infections compared to the HRV-associated cases that survived. Among the HRV species, HRV-C compared to HRV-A cases were older (12.1 vs. 9.4 months, P=0.033), more likely to present with wheeze (35% vs. 25%, P=0.031) and 2.59-fold (aOR 95% CI: 1.23-5.95) more likely to be associated with viraemia (12% vs. 2%, P=0.025). Conversely, the HRV-A infected cases were more likely to have radiographically confirmed pneumonia (46%) compared to HRV-C infected cases (36%, P=0.040) and HRV-A mono-infected cases were more likely to have hospital stay of >3 days (72%) than HRV-C mono-infected cases (54%, P=0.039). Conclusion: HRV detection, especially among children 1-5 years of age, was associated with severe lower respiratory tract infection; however, HRV detection was ubiquitous with a high degree of genetic diversity among both cases and controls. Thus the true etiologic role of HRV during childhood disease, especially among infants, remains uncertain. Nonetheless, HRV nasopharyngeal viral loads ≥4log10 copies/mL in conjunction with HRV viraemia are potential markers for HRV-associated severe respiratory disease. Among cases, HRV-A was associated with radiographically confirmed pneumonia and generally more severe disease than HRV-C which was more associated with viraemia and wheezing disease. / MT2017

Includes bibliographical references.

abstract: Background: Research in animal models suggests that fish oil ingestion may impair immunity and increase risk for infection. To date there are no studies examining this relationship between fish oil ingestion and risk for infection in humans. Objective: The primary aim of this randomized, placebo-controlled, double-blind, parallel-arm study was to examine the effect of 400 mg of EPA and 200 mg of DHA, the main components of fish oil (FO) supplements, on the incidence of symptoms related to upper respiratory tract infections in healthy young females, at a large southwestern university. Design: Healthy young women between 18 and 38 years of age who were non-obese (mean BMI 23.7 ± 0.6 kg/m2) were recruited from an urban southwestern university campus. Subjects were non-vegetarians, non-smokers, and reported consuming less than one serving (3.5 oz) of fish per week. Participants (n=26) were randomized according to age, body weight, BMI, and daily n-3 fatty acid (FA) intake into two groups: FO (one gel capsule of 600 mg EPA/DHA per day) or CO (one placebo gel capsule of 1000 mg coconut oil per day). Participants completed a validated daily cold symptom survey, the Wisconsin Upper Respiratory Symptom Survey-21 for 8 weeks. Fasting blood samples measuring TNF-&#945; concentrations were taken at weeks 1 and 8, when 24-hour dietary recalls were also performed. Anthropometric measurements were recorded via bioelectrical impedance at trial weeks 1, 4, and 8. Results: The 8-week trial of FO supplementation did not significantly change the average score for perception of cold symptoms between FO and CO groups (167 ± 71 and 185 ± 56, p=0.418, respectively). Plasma TNF-&#945; levels (pg/mL) did not differ between groups (p=0.482). TNF-&#945; levels were significantly correlated with body weight (r=0.480, p=0.037), BMI (r=0.481, p=0.037, and percent body fat (r=0.511, p=0.025) at baseline. Conclusions: Healthy young women taking a fish oil supplement of 400 mg EPA and 200 mg DHA per day over 8 weeks does not impose unintentional health consequences. These findings do not refute the American Heart Association's current recommendations for all Americans to consume two servings (3.5 oz) of a variety of oily fish per week. Depending on the type of fish, this current recommendation equates to approximately 200-300 mg per day of EPA and DHA n-3 polyunsaturated fatty acids. Additional research is needed to investigate the effects of higher dosages of fish oils on daily cold symptoms. / Dissertation/Thesis / M.S. Nutrition 2013

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Temperature has been known to be an important factor for in vitro studies where human cell cultures are infected with HRV (human Rhinovirus). The mechanisms behind the temperature effect on the struggle between virulence and cellular defense, are still largely unknown and may be a crucial part in finding a treatment to the common cold. In this study we focused on a few cellular key elements in this struggle and observed behavior changes in regards to the pre-infection growth temperature and the temperature during the viral infection. Past studies have focused mainly on the temperature post inoculation, but here we also wanted to correlate virulence to the growth temperatures preceding the viral infection. We found that the growth temperature of the cell did indeed affect its response to the HRV. If the cells had been growing in an optimal body temperature of 37°C before getting virally infected at 33°C, the viability of the cells did decrease in comparison to cells that had been growing in 33°C from before the viral infection. We could also observe a significant temperature dependence regarding IL-8 release upon HRV inoculation. HRV strive to block induction of inflammatory cytokines such as interferons and IL-1. It may be that impaired IL-8 release at lower temperatures will prevent important danger signals alerting the immune system when cytokine signaling is otherwise hampered by viral intervention.

abstract: The antioxidant, antihistamine, and chemotactic properties of vitamin C provide the theoretical basis linking vitamin C supplementation to combating the common cold; yet, the clinical evidence is mixed. To date, vitamin C intervention trials have not systematically recorded cold symptoms daily or looked at fluctuations in plasma histamine over an extended period. Also, trials have not been conducted in individuals with marginal vitamin C status. This study examined the impact of vitamin C supplementation during cold season on specific cold symptoms in a population with low plasma vitamin C concentrations. Healthy young males who were not regular smokers or training for competitive sports between the ages of 18 and 35 with below average plasma vitamin C concentrations were stratified by age, body mass index, and vitamin C status into two groups: VTC (500 mg vitamin C capsule ingested twice daily) or CON (placebo capsule ingested twice daily). Participants were instructed to fill out the validated Wisconsin Upper Respiratory Symptom Survey-21 daily for 8 weeks. Blood was sampled at trial weeks 0, 4, and 8. Plasma vitamin C concentrations were significantly different by groups at study week 4 and 8. Plasma histamine decreased 4.2% in the VTC group and increased 17.4% in the CON group between study weeks 0 and 8, but these differences were not statistically significant (p>0.05). Total cold symptom scores averaged 43±15 for the VTC group compared to 148±36 for the CON group, a 244% increase in symptoms for CON participants versus VTC participants (p=0.014). Additionally, recorded symptom severity and functional impairment scores were lower in the VCT group than the CON group (p=0.031 and 0.058, respectively). Global perception of sickness was 65% lower in the VTC group compared to the CON group (p=0.022). These results suggest that 1000 mg of vitamin C in a divided dose daily may lower common cold symptoms, cold symptom severity, and the perception of sickness. More research is needed to corroborate these findings. / Dissertation/Thesis / M.S. Nutrition 2012

abstract: The common cold is a significant cause of morbidity world-wide, with human rhinovirus infections accounting for a majority colds suffered each year. While the symptoms of the common cold are generally mild and self-limiting, vulnerable populations such as individuals with asthma can experience severe secondary complications including acute asthma exacerbation which can result in severe morbidity. Most human rhinovirus types utilize Intercellular Adhesion Molecule-1 (ICAM-1) as a receptor to enter cells and initiate infection. Expression of this cell-surface protein is elevated in the respiratory tract of asthma patients. The theoretical basis for this research is the observation that plasma measures of the soluble form of Intercellular Adhesion Molecule-1 (sICAM-1) decrease in response to vitamin C supplementation. As rhinovirus infection occurs in the upper respiratory tract, the primary aim of this study was to evaluate change in sICAM-1 concentration in nasal lavage of asthmatic individuals in response to vitamin C supplementation. Otherwise healthy asthmatic adults between the ages of 18-65 years who were not currently using steroidal nasal sprays, smoking, or actively training for competitive sports were recruited from a university community and surrounding area to participate in an 18-day double-blind randomized placebo-controlled supplement study with a parallel arm design. 13 subjects were stratified based on age, gender, BMI and baseline plasma vitamin C level to receive either 500 mg vitamin C twice daily (VTC, n=7) or placebo (PLC, n=6). Biochemical measures included nasal lavage sICAM-1, plasma sICAM-1, plasma histamine, and plasma vitamin C. Survey measures included Wisconsin Upper Respiratory Symptom Survey-21 to assess colds, Daytime Symptom Diary Scale to assess asthma symptoms, and measures of diet quality including a vitamin C food frequency questionnaire and Rapid Eating Assessment for Participants. No between group comparison of means reached significance (Mann-Whitney U test, p>0.05). Nasal lavage sICAM-1 levels were decreased in VTC group by 37% at study day 4, although this finding did not reach significance. Findings in this study can be used to develop future investigations into the response of nasal lavage sICAM-1 to vitamin C supplementation. / Dissertation/Thesis / Masters Thesis Nutrition 2014