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The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis. A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%). Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB� The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively. For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively. IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes). In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.

Background Findings for the association of prenatal maternal infections and schizophrenia are inconsistent. Whether specific maternal infections may contribute to central nervous system dysfunction, like schizophrenia remains unknown. Thus, a systematic review is conducted to clarify the role of infections on the pathogenesis of schizophrenia. Methods A manual and electronic search of the literature for prenatal maternal infection at the individual level and the diagnosis of schizophrenia in offspring was conducted. All the included studies are searched from PubMed and EMBASE databases and generally based on population level datasets with cohort or nested case-control studies designs. We only focus on three kinds of maternal infections in the review (i.e. influenza pandemic, rubella and Toxoplasmosis), other infections such as herpes simples, varicella‐zoster virus and polio were excluded. Positive family history of psychotic illness was excluded as genetic disposition is established as a strong risk factor of developing schizophrenia in offspring. Results Fifteen studies were included in this systemic review. Nine (60%) of these studies reported a positive association between maternal infections and the development of schizophrenia in the later lives of their offspring, while six (40%) of these studies indicated that there is no significant difference among cases of schizophrenia in maternal infections exposure and the control subjects or no association between schizophrenia in offspring and the infections during pregnancy as the exposure. Among all the studies, thirteen cohort studies and two nested‐case studies were examined. Eight (61.5%) showed a positive association, meanwhile five (38.5%) showed a null association. Two nested‐case control studies both suggested that maternal infection exposure is a risk factor for schizophrenia. Conclusion Findings for the association of prenatal maternal infections and schizophrenia are not equal to the evidence for causation. Due to the absence of external validity due to small and non‐representative samples, selection bias was suspected even with a significant result. Additionally, multiple exposures were hard to testify during pregnancy. Even we adjusted for the measured confounders, residual confounding such as genetic disposition and socioeconomic status, as well as unmeasured confounding are concerns. Quasi-experimental methods may help improve causal inference such as the use of instrumental variable analysis in future studies. Preventive strategies such as immunizations need to be deliberated carefully to weight the benefit and the potential impact. / published_or_final_version / Public Health / Master / Master of Public Health

The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis. A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%). Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB� The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively. For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively. IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes). In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.

MSc., Faculty of Science, University of the Witwatersrand, 2011 / Background: Due to the high cost and limited serotype coverage of pneumococcal conjugate vaccines (PCV), surface proteins of Streptococcus pneumoniae are being investigated for their role as potential vaccine candidates. There are limited data on natural antibody kinetics against pneumococcal surface proteins arising through exposure to pneumococcal nasopharyngeal (NP) colonization in African populations. Objectives: To characterize the natural antibody kinetics and sero-prevalence to 15 pneumococcal proteins with respect to age, PCV vaccination and HIV status as well as to explore the association between antibody titers and pneumococcal nasopharyngeal colonization in infants, older children and adults. Methods: We established a 15-plex Luminex assay for the following proteins: PspA, PspC, LytB, IgA1-proteinase, SP 0082, PdB, PcsB, PsaA, SP 0609, SP 0749, PpmA, SlrA, StkP, SP 2027 and SP 2194, and also validated the Luminex assay comparing it to a standard ELISA method for PspA, PspC, PsaA and PdB. We used the Luminex method to characterize the prevalence and dynamics of serum IgG antibodies against the pneumococcal proteins. The study involved 2 166 human subjects which included: i. A longitudinal cohort of children less than 2 years of age, who were vaccinated with the seven-valent pneumococcal conjugate vaccine (PCV-7) and were either a) HIV-exposed infected, b) HIV-exposed uninfected or c) HIV-unexposed uninfected. ii. A longitudinal cohort of PCV-7 unvaccinated children less than 2 years of age who were either: a) HIV-unexposed uninfected or b) HIV-exposed uninfected. The PCV-7 vaccinated and unvaccinated children were followed up from approximately 4 to 24 months of age. In addition, samples were also analyzed from HIV-uninfected and HIV-infected children Project ID: Pneumococcal protein antigens Student: Zanele Ditse Date: 04 October 2011 - 5 - aged between 4 to 7 years who received either a primary series of PCV-9 or placebo during infancy. Lastly, we analyzed cross-sectional samples from HIV-uninfected and HIV-infected women. Results: The multiplex Luminex assay correlated well with singleplex ELISAs for all four analyzed proteins with correlation coefficients of 0.86, 0.90, 0.87 and 0.96 for PspA, PspC, PdB and PsaA respectively. Antibody titers to PspC, PdB, LytB, SP 0082, PcsB and StkP showed increases in titer with respect to increasing age. Prevailing nasopharyngeal pneumococcal colonization in young children was associated with higher antibody titers to PspA, PspC, PdB, SP 0082, LytB, IgA1-proteinase, PpmA, PcsB and StkP. Conversely higher antibody titers to PspC, PdB, LytB, SP 0082, PcsB and StkP were associated with lower prevalence of pneumococcal colonization in older children and adults. In children under two years of age, PCV vaccination was associated with lower antibody titers to PspA, PspC, LytB, PdB, IgA1-proteinase, PcsB and StkP as well as higher antibody titers against SP 0082 and PpmA at multiple time-points. In PCV-vaccinated children under two years of age, those who were HIV-unexposed , -uninfected had higher antibody titers to PspA, PspC, SP 0082, IgA1-proteinase, PpmA and StkP compared to HIV-exposed, uninfected children. Conclusion: There was an age-related increase in antibody titers to PspA, PspC, PdB, SP 0082, LytB, IgA1-proteinase, PpmA, PcsB, and StkP in children under two years of age. PCV immunization was, however, associated with lower antibody titers to PspA, PspC, LytB, PdB, IgA1-proteinase, PcsB and StkP in young children which was not attributed to differences in the prevalence of nasopharyngeal colonization. Furthermore, HIV-infection status in young children was associated with higher antibody responses to PspA, PspC, PdB, SP 0082, LytB, IgA1-proteinase, PpmA, PcsB and StkP proteins in HIV-unexposed uninfected children compared to HIV-exposed uninfected and HIV-exposed infected children. Higher antibody concentrations to Project ID: Pneumococcal protein antigens Student: Zanele Ditse Date: 04 October 2011 - 6 - PspC, PdB, LytB, SP 0082, PcsB and StkP was negatively associated with nasopharyngeal pneumococcal colonization in older children and adults; indicating a protective role against colonization and a potential role as vaccine candidates.

M. Tech. Food Technology. / Problems to be solved in this project was to validate isolation and detection methods for C. koseri; to assess the environmental prevalence of C. koseri by testing a range of raw South African food products and to determine the specific risk of neonatal infections by monitoring powdered infant formula on the South African market for the presence of this organism.

Fungal infections are ignored by social and political communities. However, they are estimated to affect more than a billion people, resulting in approximately 11.5 million life-threatening infections in the 'at risk' population and more than 1.5 million deaths annually. Though there have been huge advances in diagnostics and antifungal drug development over the past two decades, however, resource limited settings have not benefited from these advances. The aim of this research was to determine the burden of serious fungal infections in Nigerians with the appropriate underlying diseases. This epidemiological research was conducted across four study populations. Study 1; HIV-infected patients with CD4+ counts < 250 cells/mm³, irrespective of their ART status, a CrAg lateral flow assay was used for detecting cryptococcal antigenaemia (n=214). Study 2; a cross-sectional multicentre survey of TB patients being managed for smear negative or treatment failure TB irrespective of their HIV status (n=208). Study 3; a multicentre histoplasmin skin sensitivity survey amongst healthy HIV-infected and non-HIV infected participants; intradermally; induration ≥ 5 mm was considered to be histoplasmin positive (n=750). Study 4; a prospective cohort study of critically ill patients in a Nigerian ICU (n=71). Two retrospective studies to analyse the clinical picture of serious fungal infections in two at risk populations (HIV/AIDS and neonatal intensive care babies) in Nigerians was also conducted (n=7034; n=2712 respectively). Results revealed an overall seroprevalence of cryptococcal antigenemia of 8.9% with 6 (9.8%) in those with CD4+ cell counts < 100cells/mm³, 4 (5.0%) in the 100-200 group and 9 (12.3%) in 200-250 cells/mm³ group; a CPA prevalence of 8.7% (6.5% had HIV infection and 14.5% were HIV-negative) and a prior subclinical histoplasmosis of 4.4%. The ICU study revealed a 45% healthcare associated infection rate representing an incidence rate of 79/1000 patient-days in the ICU. The retrospective studies revealed a 2.3% rate of neonatal ICI with a case fatality rate of 18.5%. In the 12 years retrospective study 18% had a fungal OI with 88% of patients having initiated ART. In conclusion, serious fungal infections do occur in the at risk population in Nigeria and they constitute a significant public health challenge. Our findings demonstrate that there has been an underestimation of the burden of the problem in Nigerians. There is a dire need to design guidelines for the management of fungal infections in at risk population.

Yes / Background: Group B Streptococcus (GBS) is a leading cause of morbidity and mortality in infants in both developed and developing countries. To our knowledge, only a few studies have been reported the clinical features, treatment and outcomes of the GBS disease in China. The severity of neonatal GBS disease in China remains unclear. Population-based surveillance in China is therefore required. Methods: We retrospectively collected data of <3 months old infants with culture-positive GBS in sterile samples from three large urban tertiary hospitals in South China from Jan 2011 to Dec 2014. The GBS isolates and their antibiotic susceptibility were routinely identified in clinical laboratories in participating hospitals. Serotyping and multi-locus sequence typing (MLST) were also conducted for further analysis of the neonatal GBS disease. Results: Total 70 cases of culture-confirmed invasive GBS infection were identified from 127,206 live births born in studying hospitals, giving an overall incidence of 0.55 per 1000 live births (95% confidence interval [CI] 0.44–0.69). They consisted of 49 with early-onset disease (EOD, 0.39 per 1000 live births (95% CI 0.29–0.51)) and 21 with late-onset disease (LOD, 0.17 per 1000 live births (95% CI 0.11–0.25)). The incidence of EOD increased significantly over the studying period. Five infants (4 EOD and 1 LOD) died before discharge giving a mortality rate of 7.1% and five infants (7.1%, 2 EOD and 3 LOD) had neurological sequelae. Within 68 GBS isolates from GBS cases who born in the studying hospitals or elsewhere, serotype III accounted for 77.9%, followed by Ib (14.7%), V (4.4%), and Ia (2.9%). MLST analysis revealed the presence of 13 different sequence types among the 68 GBS isolates and ST-17 was the most frequent sequence type (63.2%). All isolates were susceptible to penicillin, ceftriaxone, vancomycin and linezolid, while 57.4% and 51.5% were resistant to erythromycin and clindamycin, respectively. Conclusions: This study gains the insight into the spectrum of GBS infection in south China which will facilitate the development of the guidance for reasonable antibiotics usage and will provide evidence for the implementation of potential GBS vaccines in the future. / Supported by medical and health science and technology projects of Health and Family Planning Commission of Guangzhou Municipality (grant number 20151A010034) and Guangdong provincial science and technology planning projects (grant number 2014A020212520).

A total of 338 infants with suspected clinical sepsis were investigated, 115 of whom were found to be clinically infected. Twenty-one healthy term neonates were recruited as control subjects. The expression of CD64 on neutrophils in infected infants was significantly elevated at both 0 h and 24 h, compared with those of noninfected infants or controls (both p &lt; 0.0005). The calculated optimal cutoff value for CD64 was 6136 antibody-phycoerythrin molecules bound/cell. CD64 has a very high sensitivity (96%) and NPV (97%) at 24 h. The use of CRP in combination with CD64 as predictive markers only marginally enhanced the sensitivity and NPV (97% and 98%, respectively). There was no statistical difference in the expression of monocyte HLA-DR among infected, noninfected, and control subjects. As a result, the optimal cutoff value for HLA-DR could not be determined. The technology of flow cytometry has potential applications for use in the diagnosis of neonatal sepsis because the measurement is quantitative, requiring only a minimal amount of whole blood and a short duration (within 3 h) for the provision of results. (Abstract shortened by UMI.) / Term newborns in whom infection was suspected when they were &lt;72 h of age were recruited into the study. The expressions of CD64 on neutrophils and HLA-DR on monocytes were measured by flow cytometry at 0 h (the time of sepsis evaluation) and 24 h after the onset of presentation. A full sepsis screen, including complete blood count, serial C-reactive protein (CRP), blood culture, cerebrospinal fluid culture, and chest radiograph were performed. The demographic and clinical data were documented. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of neutrophil CD64, monocyte HLA-DR and the combination of markers for predicting neonatal sepsis were determined. / This prospective study aimed to evaluate the diagnostic utilities of two cell surface markers, neutrophil CD64 and monocyte HLA-DR, for the identification of early-onset clinical infection and pneumonia in term infants. The optimal cutoff value of each marker was defined according to the Receiver Operating Characteristic curve so that it could be used as a reference with which future studies can be compared. / Li Geng. / "May 2005." / Adviser: Pak Cheung Ng. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0174. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 129-150). / 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.

Thesis (MScMedSc)--Stellenbosch University, 2012. / Includes bibliography / ENGLISH ABSTRACT: Infection is a major cause of morbidity and mortality in infants within the first few months of life. Susceptibility to infectious disease in this vulnerable population is more prevalent in resource-limited regions, with a higher disease burden. Due to certain deficiencies in their adaptive immune system, neonates rely predominantly on their innate immune system for protection against infection, a vital component in the early host defence against pathogens. Several studies have described differences in neonatal innate toll-like receptor-mediated responses compared to adult counterparts, though very little is known about these receptor responses within resource-limited settings. To address this issue, we assessed the longitudinal development of cytokine-specific responses of TLR4 and TLR7/8 in monocytes, myeloid dendritic cells and plasmacytoid dendritic cells in infants from a resource-limited setting, South Africa, within the first 12 months of life and compared it to adults. Contrary to previously published literature, we observed heightened production of TH-1 cytokines: we showed increased responsiveness to TLR4 and TLR7/8 stimulation in infants at two and six weeks of age, which may be due to vaccination administered at birth. Unexpectedly, the hyper-inflammatory response persisted at six months in response to the LPS (TLR4) stimulus. This increased response at six months may be attributed to decreased passive immunity through infant weaning as well as increased exposure to microbial pathogens in this setting. Maturation of most cytokine responses was reached at twelve months for the TLR4 receptor, and at six months for the TLR7/8 receptor. The first year of life represents a critical period for maturation of the immune response. Data from this study point towards an elevated response within the first six months of life. This heightened response reflects both an ability to mount a sufficient TH-1 response in infancy, but more likely, the increased exposure to microbial stimuli in the environment. Thus, we speculate that these age-specific inflammatory responses may influence the outcome of immune responses to various vaccines administered, which may result in altered responsiveness to immunisation in infancy. / AFRIKAANSE OPSOMMING: Die hoof oorsaak vir morbiditeit en mortaliteit in babas binne die eerste paar maande van hul lewe word toegeskryf aan infeksie. In hulpbron beperkte gebiede, gekenmerk deur `n groter siektelas, is daar `n verhoogde vatbaarheid vir infeksie in hierdie kwesbare populasie. As gevolg van sekere gebreke in die verworwe immuunstelsel, maak pasgebore babas hoofsaaklik staat op hul aangebore immuunstelsel vir beskerming teen infeksie, ’n belangrike komponent vir die vroeë verdediging teen patogene. Verskeie studies het al die verskille in toll-tipe reseptor (TTR) bemiddelde reaksies tussen pasgebore babas en volwassenes vergelyk, maar nie veel is bekend oor hierdie reaksies in areas waar hulpbronne beperk is nie. Om hierdie kwessie aan te spreek is die longitudinale ontwikkeling van sitokien-spesifieke reaksies van die TTR4 en TTR7/8 reseptore van monosiete, miëloïede en plasmasitoïede dendritiese selle van babas in die hulpborn beperkte land Suid-Afrika, oor die eerste 12 maande geëvalueer en dit vergelyk met volwassenes. In teenstelling met vorige literatuur, het hierdie studie ’n polarisasie tot TH-1-sitokien produksie gevind: verhoogde reaktiwiteit van die TTR4 en TTR7/8 is gevind in babas van twee en ses weke oud, wat gedeeltelik as gevolg van die inenting kan wees wat toegedien was na geboorte. Hierdie hiper-inflammatoriese reaksie teen die TTR4 stimulus (Lipopolisakkaried (LPS), het teen verwagting voortgeduur tot op ses maande en kan toegeskryf word aan die vermindering van passiewe immuniteit deur spening, sowel as die toenemende blootstelling aan mikrobiese patogene in die omgewing. Maturasie vir die meerderheid van die sitokiene reaksies, is bereik op 12 maande vir TTR4, en op ses maande vir TTR7/8. Die eerste lewensjaar is ‘n kritiese periode vir die ontwikkeling van die immuunstelsel. Data van hierdie studie dui op ‘n verhoogde reaksie binne die eerste ses maande van ‘n baba se lewe. Hierdie verhoogde reaksie dui op die vermoë om `n voldoende TH-1 reaksie te ontlok, maar meer waarskynlik, verhoogde blootstelling aan mikrobiese stimuli in die omgewing. Dus spekuleer ons dat hierdie ouderdom-spesifieke reaksies dalk die uitkoms van die immuunreaksie teen verskeie entstof toediening kan beïnvloed in babas.