Thesis (Ph. D.)--University of Wisconsin, 1947. / Typescript (carbon copy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 127-145).

emezones@gmail.com / Introduction: Pneumococcal pneumonia (PP) has a high burden of morbimortality in children. Use of pneumococcal conjugate vaccines (PCVs) is an effective preventive measure. After PCV 7-valent (PCV7) withdrawal, PCV 10-valent (PCV10) and PCV 13-valent (PCV13) are the alternatives in Peru. This study aimed to evaluate cost effectiveness of these vaccines in preventing PP in Peruvian children <5 yearsold. Methodology: A cost-effectiveness analysis was developed in three phases: a systematic evidence search for calculating effectiveness; a cost analysis for vaccine strategies and outcome management; and an economic model based on decision tree analysis, including deterministic and probabilistic sensitivity analysis using acceptability curves, tornado diagram, and Monte Carlo simulation. A hypothetic 100 vaccinated children/vaccine cohort was built. An incremental cost-effectiveness ratio (ICER) was calculated. Results: The isolation probability for all serotypes in each vaccine was estimated: 38% for PCV7, 41% PCV10, and 17% PCV13. Avoided hospitalization was found to be the best effectiveness model measure. Estimated costs for PCV7, PCV10, and PCV13 cohorts were USD13,761, 11,895, and 12,499, respectively. Costs per avoided hospitalization were USD718 for PCV7, USD333 for PCV10, andUSD 162 for PCV13. At ICER, PCV7 was dominated by the other PCVs. Eliminating PCV7, PCV13 was more cost effective than PCV10 (confirmed in sensitivity analysis). Conclusions: PCV10 and PCV13 are more cost effective than PCV7 in prevention of pneumonia in children <5 years-old in Peru. PCV13 prevents more hospitalizations and is more cost-effective than PCV10. These results should be considered when making decisions about the Peruvian National Inmunizations Schedule. / This study was funded by Instituto Nacional de Salud, Lima, Peru / Revisión pór pares

A Research report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in Paediatrics Johannesburg 2015 / Children hospitalized with culture-confirmed pulmonary tuberculosis (PTB) frequently present with acute symptoms, possibly because underlying PTB may predispose to superimposed bacterial pneumonia. Immunization of children with pneumococcal conjugate vaccine (PCV) could protect against such superimposed bacterial pneumonia and reduce the incidence of PTB hospitalization. OBJECTIVE We studied the temporal association of childhood immunization with pneumococcal conjugate vaccine on the incidence of hospitalization for culture-confirmed PTB in children. METHODS A retrospective study on the incidence of hospitalization for culture-confirmed childhood PTB at Chris Hani Baragwanath Academic Hospital was undertaken from 2005 to 2012. This included a pre-PCV era (2005-2008) and a PCV era (2011-2012). RESULTS Overall, there was a 69.2% (95% CI: 62.8-74.6%) decline in the incidence of hospitalization for culture-confirmed PTB when comparing the PCV and pre-PCV-eras, with the decline in HIV-uninfected children only significant in the 3-11 month age category and the decline in HIV-infected significant across all age categories. There was a trend for reduced pneumococcal bacteraemia in the PCV era compared to the pre-PCV era, with the odds of having a blood culture positive for pneumococcus being 1.91-fold (95% CI, 0.26-84.56) greater in the Pre-PCV era. CONCLUSION There has been a significant decline in culture-confirmed PTB hospitalization in children comparing the pre-PCV to the PCV-era. However, the incidence of culture-confirmed PTB prior to the introduction of PCV had been reduced to low levels due to antiretroviral therapy. This confounder together with the retrospective ecological study design and other several possible confounders limited any robust estimate as to whether there was a temporal association between PCV immunization and incidence of culture-confirmed PTB hospitalization in our study setting.

BACKGROUND: After the introduction of PCV7 and PCV13, the number of cases of pneumonia in children caused by vaccine serotypes has decreased significantly. Children with comorbidities, however, are still at high risk for IPD. This study aims to compare children with comorbidities to healthy children in an urban setting to assess current risk factors and potential risk factors for pneumonia. METHODS: Existing clinical data of Boston Medical Center patients under 7 years of age were used to compare age, gender, race, comorbidities, and immune status of children with pneumonia to those of children without pneumonia. A representative random sample of 150 patients with pneumonia and 150 patients without pneumonia was selected. Medical record and chart information were reviewed in order to obtain clinical and demographic data. RESULTS: In our study cohort, 120 of 300 (40%) children whose charts were reviewed had at least one comorbidity. Among 150 children with pneumonia, 76 (50.7%) cases were found to have at least one underlying condition, whereas in children without pneumonia 44 (29.3%) of 150 cases had at least one underlying clinical condition (chi-square value 14.2; p-value <0.001). Children with comorbidities were 2.47 times more likely to have pneumonia compared to children without any chronic conditions (OR 2.47, 95% CI 1.54 - 3.98). The risk of having pneumonia among children who are not Hispanic/Latino/Spanish was approximately 40% less compared to children of Hispanic origin (OR 0.61; 95% CI 0.31 - 1.19; p-value 0.14). CONCLUSIONS: Our study shows that children with underlying conditions are at greater risk for pneumonia compared to healthy children without chronic conditions. Ethnicity is also associated with pneumonia cases, with Hispanic children at increased risk for pneumonia compared to non-Hispanic children.

No description available.

Thesis (M.Med.(Paediatrics), Faculty of Health Sciences, University of the Witwatersrand, 2009 / Background In settings with a high burden of tuberculosis, children with unrecognised culture-confirmed pulmonary tuberculosis (PTB) may be discharged from hospital before mycobacterial culture results are available; in these cases clinical improvement may have been due to successful treatment of an intercurrent viral or bacterial co-infection. Aim To estimate the burden of tuberculosis in children who were enrolled in a double-blind, placebo-controlled pneumococcal conjugate vaccine (PCV) trial, and to probe for the presence of pneumococcal co-infection in trial participants who had a hospital-based diagnosis of PTB. Methods A retrospective case-finding strategy was adopted in order to define the tuberculosis case load amongst 39 836 children that had been enrolled in a PCV efficacy trial in Soweto, Gauteng Province. The trial follow-up period was 5.3 years. Children with a hospital-based diagnosis of tuberculosis were categorised by strength of evidence for the disease, HIV status and PCV vaccination status. Incidence rates and risk ratio assessments were conducted using standard statistical methods. Results Four-hundred and ninety-two episodes of tuberculosis arose amongst 425 of the 39 836 PCV Study participants. Tuberculosis incidence was 1067 per 100 000 children (95% Confidence Interval [CI], 968 – 1173), with the greatest burden observed amongst HIV-infected children (10 633 per 100 000 children [95% CI, 9411 – 11 969]; Risk Ratio [RR] 27.5 [95% CI, 22.6 – 33.5], P<0.001). The burden of PTB in the cohort was 982 cases per 100 000 children (95% CI, 887 – 1084): 9895 per 100 000 (95% CI, 8718 – 11 187) in the HIV-infected children and 352 per 100 000 (95% CI 294 – 417) in the HIV-uninfected children (RR 28.1; 95% CI, 22.9 – 34.6), P<0.001. PCV recipients exhibited a 44 percent (95% CI, 11 – 65), P=0.010, reduction in incident culture-confirmed PTB compared to placebo recipients; this apparent reduction was demonstrated chiefly in PCV-vaccinated HIV-infected children (RR 0.53; 95% CI, 0.31 – 0.90) compared to HIV-infected placebo recipients, P=0.017. Conclusions A high burden of tuberculosis is carried by children under 5.3 years in the study setting, with HIV-infected children bearing the brunt of the morbidity. Pneumococcal co-infections are common in the context of hospitalised PTB in the study setting.

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. / Background: Nasopharyngeal colonisation is a pre-requisite for developing bacterial respiratory and invasive disease. Immunisation of children with the pneumococcal conjugate vaccine (PCV) impacts upon colonising pneumococcal serotypes, which in turn could also affect the biome of the nasopharynx in relation to colonisation by other bacteria. Due to limitations in standard culture methods, the association between PCV-immunisation and bacterial carriage density is still unclear, including among HIV-infected children. In this study we aimed to evaluate the effect of infant vaccination with the 7-valent PCV (PCV7) on vaccine-serogroup colonisation in order to determine whether the increase in non-vaccine serotype (NVT) colonisation was due to unmasking of previously low density colonising serotypes or increase in acquisition of NVT. Also, we evaluated the association between PCV7 immunisation and HIV-infection on the prevalence density of nasopharyngeal colonisation by other common potentially pathogenic bacteria. Methods: A multiplex real-time qPCR assay was set up to detect 44 common pneumococcal serotypes and 5 bacterial pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes. All assays were optimised according to MIQE guidelines and their ability to detect multiple pneumococcal serotype/group and bacteria in archived nasopharyngeal swabs were evaluated. The multiplex qPCR assays were then used to evaluate vaccine-serotype, non-vaccine serotype and bacterial nasopharyngeal colonisation in achieved swabs of PCV7-vaccinated (at 6, 10 and 14 weeks of age) and PCV-unvaccinated African children at 9 and 15-16 months of age, prior to routine vaccination of children with PCV through the public immunisation program. In order to address the limitations of the qPCR assays, a nanofluidic real-time PCR assay was developed to simultaneously detect 53 pneumococcal serotypes, 6 serotypes of H. influenzae and 11 bacterial pathogens. Further, all assays were optimised and evaluated according to the MIQE guidelines and findings from Fluidigm and traditional qPCR assays were compared. Lastly, Fluidigm was used to evaluate the association of HIV-infection on the prevalence and density of nasopharyngeal colonisation at 9 and 16 months of age by common, potentially pathogenic bacteria including PCV7 pneumococcal serotypes, non-PCV7 serotypes, Haemophilus influenzae, non-typable Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus pyogenes, Neisseria meningitidis, Neisseria lactamica, Bordetella pertussis, Bordetella parapertusis, Bordetella bronchiseptica and Bordetella holmesii in achieved nasophartngeal swabs collected from PCV7-vacciniated HIV-infected and HIV-uninfected children. Results: Molecular qPCR was more sensitive than culture in detecting multiple concurrent colonising pneumococcal serotypes as well as other common nasopharyngeal colonisers, with the majority of additional isolates detected by qPCR having a low carriage density (<104 CFU/ml). Further, qPCR identified a lower prevalence of PCV7-serotype colonisation among PCV7-vaccinated compared to PCV-unvaccinated children at 9 and 16 months of age [adjusted Odds Ratio (aOR): 0.37; 95% CI; 0.19-0.7 and 0.41; 95% CI; 0.26-0.63, respectively]; and an increase in NVT-serotype [aOR: 1.88; 95% CI; 1.02-3.48 and 2.2; 95% CI; 1.18-4.1] colonisation respectively. The increase in NVT carriage among PCV7-vaccinees was driven by serotype 19A, which increased by 53.4% (p=0.021) and 70.7% (p<0.001) at 9 and 16 months of age respectively. Further, 19A had a higher density of colonisation in PCV7-vaccinated groups compared to PCV-unvaccinated groups and was more likely to be identified as a primary than non-primary isolate in PCV7-vaccinated children alone. PCV immunisation was also associated with an increased prevalence of H. influenzae at 9 months (55.8% vs. 66.3%, p<0.001) and 16 months (72% vs. 62%, p=0.017) of age, while a temporary increase in the carriage prevalence of S. aureus was found in PCV7-vaccinated (18.9%) compared to PCV-unvaccinated children (11.1%, aOR 2.1; 95% CI 1.0-1.4; p=0.049) at 9 months of age only. The density of pneumococcus (4.68 vs. 4.28 CFU/ml; p=0.007), H. influenzae (3.86 vs. 4.34 CFU/ml; p=0.008), M. catarrhalis (2.98 vs. 3.52 CFU/ml; p<0.001) and S. aureus (3.06 vs. 4.02 CFU/ml; p=0.02) were also higher among PCV7-vaccinated compared to PCV-unvaccinated children at 9 months age, although this difference diminished with increasing age. There was excellent concordance between the qPCR and Fluidigm for carriage prevalence and density of the majority of assays, with Fluidigm identifying an additional 7 pneumococcal serotypes and 11 bacterial species above those detected by qPCR. Further, discordant results between the two PCR methods were strongly associated with a low carriage density (<102 CFU/ml). Using molecular Fluidigm, a lower carriage prevalence of overall pneumococci (58.6% vs. 69.9%; p=0.02), non-vaccine serotypes (27.8% vs. 40%; p=0.047) and H. influenzae (64.2% vs. 42.3%; p=0.01) was identified in HIV-infected children compared to HIV-uninfected children who were immunised with PCV7 at 9 months of age. No difference in the carriage prevalence of overall pneumococci was however found at 16 months of age (p=0.20), although the carriage prevalence of non-vaccine serotypes (50.9% vs. 60.4%; p=0.049) and H. influenzae (56% vs. 73.4%; p=0.02) was lower in HIV-infected children at 16 months of age. In addition, the density of overall pneumococcus was found to be higher in HIV-infected children (4.81 vs. 4.44 CFU/ml; p=0.014), despite the lower carriage prevalence at 9 months of age, which was driven by a higher density of vaccine serotypes/serogroups (4.21 vs. 3.72 CFU/ml; p=0.04). By 16 months of age, there was no difference in density of pneumococcal colonisation between the HIV-infected and HIV-uninfected children (p=0.89). No difference in the density of H. influenzae was found between HIV-infected and HIV-uninfected infants at 9 months of age (p=0.08); however, by 16 months of age, HIV-uninfected children had a higher density of overall H. influenzae colonisation (4.95 vs. 4.32 CFU/ml; p<0.001), which was largely due to the higher carriage density of NThinf in HIV-uninfected children (5.0 vs. 4.23 CFU/ml; p<0.001). Conclusion: Molecular qPCR assays were shown to be a promising alternative to WHO recommended culture in that multiple pneumococcal serotypes and other bacterial pathogens could be simultaneously detected as well as the bacterial load of each colonising bacteria quantified. The mechanism behind the vaccine effect was shown to be a combination of both serotype replacement and unmasking; however, the reduction in PCV7-serotype colonisation impacted on colonisation prevalence and density of other bacterial species of the nasopharynx and the clinical relevance of this needs further exploration in relation to mucosal and invasive disease outcomes, as well as for higher valence vaccines. While the higher carriage density of overall pneumococcus in HIV-infected children, despite the lower carriage prevalence might explain the higher invasive disease burden in HIV-infected compared to HIV-uninfected children even in the era of antiretroviral therapy treatment and PCV immunisation, future studies are required to provide clarity. Nevertheless, the findings from this thesis highlight the importance of continued surveillance of the circulation of pneumococcal serotypes as well as other bacterial pathogens especially in a population with a high burden of HIV-1 infection. / MT2017

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Comparison of Post-licensure safety surveillance of 13-Valent Pneumococcal Conjugate vaccine and 7-Valent Pneumococcal Conjugate vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS). Background: On February 24, 2010, Food and Drug Administration (FDA) licensed a 13-valent pneumococcal conjugate vaccine (Prevnar 13®, [PCV13]) for use among children aged 6 weeks--71 months. The Advisory Committee on Immunization Practices (ACIP) recommended PCV13 routine vaccination of all children aged 2--59 months, children aged 60--71 months with underlying medical conditions, with PCV13 replacing PCV7 for all doses. Methods: We searched case reports to the Vaccine Adverse Event Reporting System (VAERS), a US passive surveillance system, for adverse events (AEs) reported after immunization with PCV13 vaccine from February 24, 2010 through February 24, 2011 for persons vaccinated from February 24, 2010 through December 31, 2010 and compared them with AEs reported by persons who were vaccinated with PCV7. Results: VAERS received 1503 reports of AEs after PCV13; multiple vaccines were given in 79.0% of reports. One hundred eighty (11.9%) were coded as serious, including nineteen reports of death. The most frequently reported symptoms were injection site reactions, fever, irritability and vomiting. Seven hundred fifty-eight (50.4%) reports comprised males. Most reports (37.7%) were from children 1-2 years. Total number of reports received for PCV13 was very similar to those received after vaccination with PCV7. Conclusions: AEs reported to VAERS following 13-valent pneumococcal conjugate vaccine were consistent with AEs previously observed in pre-licensure trials. We did not identify any major safety concerns or outcomes.

Thesis (Ph. D.)--University of Adelaide, Dept. of Paediatrics, 1989. / Includes bibliographical references (leaves [177-194]).