New Tuberculosis Vaccine Trials in Infants: design, diagnostics and trial site development

Tuberculosis is a major public health problem, with particularly high morbidity and mortality among infants. The only licensed TB vaccine, BCG confers only partial protection against pulmonary disease, the most common and most transmissible form of the disease. Novel TB vaccines with better efficacy are urgently needed as part of the armoury of tools to eliminate TB by 2050. To properly design and implement these trials, several factors need to be borne in mind. These include, the most suited trial population, estimates of disease incidence, cohort retention and mortality. There are also diagnostic considerations, such as the utility of the chest radiograph and the possible role of the more prevalent non-tuberculous mycobacteria in confounding TB diagnosis. Finally, there are practical factors related to selection and development of research sites with the required trial infrastructure and expertise in high burden countries. This thesis explored the factors of design of new tuberculosis vaccine trials, diagnostic considerations and process of site development

The incidence of non-tuberculous mycobacteria in Infants in Kenya

There is inadequate understanding of the epidemiology of Non-Tuberculous Mycobacteria (NTM) among infants in high tuberculosis burden countries. The objective of this study was to document the incidence and diversity of NTM disease or colonisation in sputum specimens from infants with presumptive TB, the risk factors, and clinical characteristics, in a high TB and HIV burden setting in Western Kenya. A cohort of 2900 newborns was followed for 1-2 years to assess TB incidence. TB investigations included collection of induced sputa and gastric aspirates for culture and speciation by HAIN®, Tuberculin Skin Testing (TST), HIV testing, and chest radiography. The American Thoracic Society Criteria (ATS) were applied to identify NTM disease. Among 927 (32% of 2900) with presumptive TB, 742 (80%) were investigated. NTM were isolated from 19/742 (2.6%) infants. M. fortuitum was most frequently speciated (32%). Total person-time was 3330 years. NTM incidence was 5.7/1,000 person-years, 95% CI (3.5, 8.7). Infants diagnosed with TB were more likely to have NTM isolation (odds ratio 11.5; 95% CI 3.25, 41.0). None of the infants with NTM isolated met the criteria for NTM disease. The incidence of NTM isolation was comparable to similar studies in Africa. NTM isolation did not meet ATS criteria for disease and could represent colonisation. TB disease appears to be structural lung disease predisposing to NTM colonisation

A Comparative Study on the Quality of Life of Leprosy Patients in Kilifi and Kwale Counties in Kenya

Background:Kenya at present is in the post-elimination phase of leprosy having achieved a prevalence of <1 case per 10,000 persons in 1989. In 2019 Kenya notified 163 leprosy patients, highest being in Kilifi and Kwale counties. About a quarter (26%) of the notified leprosy patients had grade 2 disability at the time of diagnosis, this being the most severe form of disability that may indicate a late diagnosis. This study aimed at assessing the quality of life of leprosy patients to guide policies and programs intended to enhance the health and well-being of leprosy patients.Materials and Methods:This was a case-control study conducted in Kilifi and Kwale Counties. For every leprosy index patient enrolled, two controls were identified within the same village to match the case. Descriptive statistics were used to summarise demographic and clinical variables. The World Health Organisation (WHOQOL-BREF) tool was used to measure the quality of life. The tool derived four (4) domains of physical health, psychological status, social relationship, and environmental profile. These were transformed into a scale between 0 to 100 for analysis. The F-test was used to compare mean scores in the four domains between cases and controls. The quality of life among the index cases against their controls was further analysed using conditional logistic regression models.Results: A total of 98 leprosy patients and 167 controls were evaluated for quality of life. On the perception of quality of life, leprosy patients had significantly lower mean transformed scores of 39 (SD 25) versus 49 (SD 25) p= <0.0001 compared to controls. Similarly, index cases had lower health satisfaction scores of 42 (SD 26) compared to controls scoring 61(SD 27) p=<0.001. Overall leprosy patients had statistically significant poorer scores on physical health, psychological health, social relationships and environmental QoL domains. Differences were most remarkable in the psychological domain, with a mean transformed score of 53 (SD 20) versus 68 (SD 16) p= < 0.0001 for controls. The overall quality of life model revealed that leprosy patients who were found to have either diabetes or hypertension enjoyed a better overall quality of life with OR of 10.98 and 1.22 respectively with a p-value <0.00001. Patients with tuberculosis and HIV presented the poorest quality of life with ORs of 0.49 and 0.14 respectively.Conclusion: The quality of life of the leprosy patients was significantly lower than that of the community controls in all the domains. Governments and communities need to prioritize rehabilitation measures such as the provision of artificial limbs, cataract surgery, and social protection disbursements to help leprosy victims improve their quality of life

The impact of the nurses', doctors' and clinical officer strikes on mortality in four health facilities in Kenya

Background: Health worker strikes are a significant threat to universal access to care globally and especially in sub Saharan Africa. Kenya's health sector has seen an increase in such industrial action. Globally there is limited data that has examined mortality related to such strikes in countries where emergency services were preserved. We sought to assess the mortality impact of an 100 day physician strike which was followed by 151 day nurses' strike and 20 day clinical officer strike in Kenya. Methods: Monthly mortality data was abstracted from four public hospitals, Kenyatta National Referral Hospital, AIC Kijabe Hospital, Mbagathi Hospital and Siaya Hospital between December 2016 and March 2018. Differences in mortality were assessed using t-tests and multiple linear regression adjusting for facility, numbers of patients utilizing the hospital and department. Results: There was a significant decline in the numbers of patients seen, comparing the non-strike and strike periods; beta (ß) coefficient - 649 (95% CI -950, - 347) p < 0.0001. The physicians' strike saw a significant decline in mortality (ß) coefficient - 19.0 (95%CI -29.2, - 8.87) p < 0.0001. Nurses and Clinical Officer strikes' did not significantly impact mortality. There was no mortality increase in the post-strike period beta (ß) coefficient 7.42 (95%CI -16.7, 1.85) p = 0.12. Conclusion: Declines in facility-based mortality during strike months was noted when compared to a non-striking facility, where mortality increased. The decline is possibly associated with the reduced patient volumes, and a possible change in quality of care. Public health facilities are congested and over-utilized by the local population majority of whom cannot afford even low cost private care. Health worker strikes in Kenya where the public health system is the only financially accessible option for 80% of the population pose a significant threat to universal access to care. Judicious investment in the health infrastructure and staffing may decrease congestion and improve quality of care with attendant mortality decline

Predictors of post neonatal mortality in Western Kenya: a cohort study

Introduction:&nbsp;to determine the predictors of mortality in infants in Siaya, western Kenya, ahead of novel tuberculosis (TB) vaccine trials in the same population. Methods:&nbsp;in a study to determine tuberculosis incidence, 2900 infants aged 0-45 days, weighing ≥ 1700g were enrolled. Four monthly follow up visits were conducted for at least 12 months. HIV testing was done at six weeks of age. Free ancillary care was provided. Deaths were reported by parents, study staff and community workers. Cox proportional Hazard analysis was used to identify risk factors. The period of analysis commenced at six weeks old and was censored at 12 months of age. Results:&nbsp;included in the analysis were 2528 infants with 2020 person years of follow up (pyo). There were 117 deaths (4.6 %). The post-neonatal mortality rate was 58 (95% CI: 48, 69) per 1000 pyo. In multivariate analysis, health facility births were protective against mortality (Hazard Ratio (HR) 0.54; 95% CI: 0.34, 0.84) and infant HIV infection at baseline was associated with increased mortality (HR 10.3; 95% CI: 6.40, 16.7). HIV uninfected infants born to HIV infected mothers had increased hazards of mortality (HR 1.73; 95% CI: 1.03, 2.90). Gender, weight at six weeks, maternal education and occupation were not significant predictors of mortality. Conclusion:&nbsp;infant mortality was high and was associated with being born outside a health facility, maternal HIV infection and HIV infection of the infant. Measures to decrease mother to child transmission and other HIV control measures need to be strengthened further to see incremental reductions in infant mortality

The incidence of tuberculosis in infants, Siaya District, Western Kenya

Background: Infants are a target population for new tuberculosis (TB) vaccines. TB incidence estimates are needed to guide the design of trials. To determine the TB incidence and cohort retention among young children using comprehensive diagnostic methods in a high burden area. Methods: Infants 0-42 days were enrolled. Through 4 monthly follow-up and unscheduled (sick) visits up to the age of 2 years, infants with presumptive TB based on a history of contact, TB symptoms or pre-determined hospitalization criteria were admitted to a case verification ward. Two induced sputa and gastric aspirates were collected for culture and GeneXpert. Mantoux and HIV tests were done. Clinical management was based on the Keith Edwards score. Cases were classified into microbiologically confirmed or radiologic, diagnosed by blinded expert assessment. Cox regression was used to identify risk factors for incident TB and study retention. Results: Of 2900 infants enrolled, 927 (32%) developed presumptive TB, 737/927 (80%) were investigated. Sixty-nine TB cases were diagnosed (bacteriologic and radiologic). All TB incidence was 2/100 person-years of observation (pyo) (95% CI: 1.65-2.65). Nine were bacteriologic cases, incidence 0.3/100 pyo. The radiologic TB incidence was 1.82/100 pyo. Bacteriologic TB was associated with infant HIV infection, higher Keith Edwards scores. Completeness of 4-month vaccinations and HIV infection were positively associated with retention. Conclusions: TB incidence was high. An all TB endpoint would require a sample size of a few thousand children, but tens of thousands, when limited to bacteriologic TB

The Incidence of Tuberculosis in Infants, Siaya District, Western Kenya

BACKGROUND: Infants are a target population for new tuberculosis (TB) vaccines. TB incidence estimates are needed to guide the design of trials. To determine the TB incidence and cohort retention among young children using comprehensive diagnostic methods in a high burden area. METHODS: Infants 0-42 days were enrolled. Through 4 monthly follow-up and unscheduled (sick) visits up to the age of 2 years, infants with presumptive TB based on a history of contact, TB symptoms or pre-determined hospitalization criteria were admitted to a case verification ward. Two induced sputa and gastric aspirates were collected for culture and GeneXpert. Mantoux and HIV tests were done. Clinical management was based on the Keith Edwards score. Cases were classified into microbiologically confirmed or radiologic, diagnosed by blinded expert assessment. Cox regression was used to identify risk factors for incident TB and study retention. RESULTS: Of 2900 infants enrolled, 927 (32%) developed presumptive TB, 737/927 (80%) were investigated. Sixty-nine TB cases were diagnosed (bacteriologic and radiologic). All TB incidence was 2/100 person-years of observation (pyo) (95% CI: 1.65-2.65). Nine were bacteriologic cases, incidence 0.3/100 pyo. The radiologic TB incidence was 1.82/100 pyo. Bacteriologic TB was associated with infant HIV infection, higher Keith Edwards scores. Completeness of 4-month vaccinations and HIV infection were positively associated with retention. CONCLUSIONS: TB incidence was high. An all TB endpoint would require a sample size of a few thousand children, but tens of thousands, when limited to bacteriologic TB