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A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science in Epidemiology (Epidemiology and Biostatistics). 2016 / Background Reducing severe acute respiratory illness (SARI)-associated mortality in African children remains a public health priority and an immense challenge. The pneumococcal conjugate vaccine (PCV) was introduced into the South African routine immunization programme in 2009. The objectives of this study were: I. To describe the demographic characteristics, clinical presentation, respiratory pathogens of children aged <5 years hospitalized with SARI in an urban (Chris Hani-Baragwanath Hospital, Soweto) and a rural (Matikwana and Mapuleng Hospitals, Mpumalanga) setting in South Africa from 2009-2013 and II. To compare the factors associated with mortality among children aged <5 years hospitalized with SARI in these two sites separately. Methods Hospitalized children with SARI were enrolled into an active, prospective sentinel surveillance program. Clinical and epidemiologic data were collected until discharge. Nasopharyngeal aspirates were tested for influenza (A and B) and eight other respiratory viruses. In-hospital case-fatality proportion (CFP) and risk factors for mortality were determined for each hospital site separately using unconditional logistic regression. Results The in-hospital CFP was significantly higher in the rural (6.9%, 103/1486) than the urban (1.3%, 51/3811) site (p<0.001). This was observed among both HIV-infected (urban: 6.6%, 17/257) vs. (rural: 12.9%, 30/233) (p=0.019) and HIV-uninfected children (urban: 0.6%, 13/2236) vs. (rural: 4.2% 36/857) (p<0.001). In the urban site the only factor that is independently associated with death on multivariate analysis was HIV infection (odds ratio (OR) 12.1, 95% confidence interval (CI) 5.8-25.2). In the rural site HIV infection (OR 3.5, 95% CI 1.7-6.9), age <1 year (OR 3.5, 95% CI 2.0-6.1) vs. 1-4 years, any respiratory virus detected (OR 0.4, 95% CI 0.2-0.6), pneumococcal infection(OR 4.5, 95% CI 1.8-10.8) and malnutrition (OR 12.8, 95%CI 1.2-134.6) were independently associated with mortality. Conclusion SARI mortality was higher in the rural setting. Even in the era of PCV availability pneumococcus is still associated with mortality in rural areas. Efforts to prevent and treat HIV infections in children and reduce malnutrition may reduce SARI deaths. / MT2017

Acute respiratory infections (ARI) are a major global cause of morbidity and mortality. Vitamin D deficiency has been reported to associate with susceptibility to ARI and with greater severity and poorer control of asthma and chronic obstructive pulmonary disease (COPD). Clinical trials of vitamin D for the prevention of ARI have yielded heterogeneous results, with some showing protection and others not. This may reflect variation in the frequency of genetic variants influencing response to vitamin D supplementation in different populations. The impact that genetic variation in the vitamin D pathway has on vitamin D status, disease phenotype and response to vitamin D supplementation in prevention of ARI has not been comprehensively investigated. Methods: I conducted: 1. A systematic review and meta-analysis of clinical studies which have investigated vitamin D as a potential therapy for ARI; 2. Three cross-sectional studies (in n=297 adult asthma patients, n=278 COPD patients, and n=272 older adults) to investigate potential environmental determinants (lifestyle and anthropometric) and genetic determinants (35 single nucleotide polymorphisms [SNP] in 11 vitamin D related genes) of serum 25-hydroxyvitamin D concentration (25[OH]D) and clinical phenotype; 3. Three prospective studies investigating the influence of genetic variation in the vitamin D pathway on a) susceptibility to ARI (main effects analysis) and b) efficacy of vitamin D supplementation for the prevention of ARI (interaction analysis). Results: My systematic review identified consistent reports of an inverse association between vitamin D status and risk of ARI in observational studies, and heterogeneous reports from clinical trials. My cross-sectional studies identified a range of classical environmental factors which predict vitamin D status in the three study populations, but did not identify any genetic variants in the vitamin D pathway that associate with vitamin D status. I identified an association between vitamin D deficiency and decreased lung function in COPD patients, but no associations between vitamin D deficiency and asthma phenotype. Finally, my analysis identified a haplotype of 5 single nucleotide polymorphisms in the vitamin D receptor (VDR) gene which significantly modify the effect of vitamin D supplementation on risk of upper respiratory infection in COPD patients. Conclusions: I identified environmental determinants that predict 25(OH)D concentrations in all three study populations, but only found an association between vitamin D deficiency and disease severity in COPD patients. Furthermore, I identified a haplotype in VDR which modifies the effect of vitamin D supplementation in COPD patients to result in a significantly reduced risk of ARI.

Severe acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002 and has subsequently spread worldwide. According to the World Health Organization, 8098 cases occurred during the outbreak, and healthcare workers accounted for 1707 (21%) of the cases. To determine the prevalence of SARS infection of healthcare workers in Taiwan, we performed a serosurvey by the recombinant protein-based enzyme-linked immunosorbent assay (ELISA) to test for immunoglobulin (Ig) G antibodies to the SARS coronavirus (SARS-CoV) among 1525 healthcare workers in 26 hospitals that admitted SARS patients in mid-May, 2003. Then, a case-control study was carried out to evaluate the risk factors of SARS infection among the healthcare workers. A total of 52 infected staffs and 78 hospital and age matched non-infected controls were recruited. The seroprevalence rate was 3.68% (58/1525) for healthcare workers. Univariate analysis showed that with the habit of drinking coffee or tea, taking care of fever patients more than 8 days, ever practice of CPR, suction of sputum, taking patient¡¦s temperature, use of P100 mask, use of N95 mask, use of face cover, use of goggles, use of gown, removing gloves after work, working in isolation area or fever screen station were significantly protective factors. In addition, eating jujube was a risk factor for SARS infection. Then, the multivariate analysis showed that use of P100 ¡]OR: 0.056, 95%CI: 0.019-0.162, p value: <0.001¡^and working in isolation area ¡]OR: 0.153, 95%CI: 0.029-0.810, p value: 0.027¡^or fever screen station¡]OR: 0.103, 95%CI: 0.011-0.963, p value: 0.046¡^were the most important protective factors for SARS infection. These findings suggest that nosocomial infection of SARS can be prevented effectively by use of P100 and the triage screening in emergency departments.

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In part ONE of this thesis, including the most up to date information on SARS virology, disease transmission, pathogenesis and laboratory diagnosis will be summarized and presented, including the results of many studies in which I have participated (these references will be underlined as they appear in text). This of course summarizes knowledge that is now known in 2006 but was largely unknown during the initial outbreak. In part TWO, six original clinical studies performed at PWH will be presented: study (1) describes the clinical manifestations and severity of SARS, and its potential to cause major hospital outbreaks; (2) demonstrates the importance of epidemiological linkage in diagnosing SARS; (3) reports the clinical outcomes of a stepwise treatment protocol, which includes the use of corticosteroid therapy as an immunomodulant; (4) demonstrates that corticosteroid therapy can retard viral clearance, and should be used judiciously; (5) demonstrates that a more robust humoral response is associated with severe SARS, thus indicating that passive immunity treatment strategies seem only suitable either during early illness or as prophylaxis; and (6) shows that SARS has few early discriminating laboratory features compared to other causes of community-acquired pneumonia, thus a high index of suspicion is needed to recognize this infection in the absence of worldwide transmission. A thorough review of the relevant published material will be included in the discussion section of each study. / Severe Acute Respiratory Syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus. It caused a global outbreak in 2003, resulting in more than 8000 infections, 700 deaths, and major social and economic disruption. In the initial phase of the SARS outbreak, the medical profession had no knowledge regarding the responsible pathogen, nor the clinical manifestations of SARS and the course of illness. There was no reliable diagnostic tool and no known effective therapy. But for the first time in medical history, we witnessed the rapid accumulation of knowledge on a disease as it evolved, which in turn assisted its management and control. / Since conducting randomized-controlled trials during the 2003 crisis was almost impossible, most of the presented studies are either descriptive or case-controlled in design. However, these studies have laid foundations for recent and future research into the clinical diagnosis and management of SARS. Moreover, the construction of the SARS clinical database has contributed to the work of other investigators, which has resulted in over thirty-six publications. It is my hope that these research endeavors can contribute to the understanding of this emerging, deadly disease. / Lee Lai Shun, Nelson. / "April 2006." / Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0205. / Thesis (M.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 264-292). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.