A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirement for the degree of Master of Medicine in Anatomical Pathology 2015 / Lymphomas are the third most common paediatric malignancy. Paediatric lymphomas (PL) demonstrate unique epidemiological characteristics compared to adult lymphomas with regard to site of involvement, histopathological spectrum, stage of disease and survival outcome. In South Africa (SA), the high prevalence of Human Immunodeficiency Virus (HIV) results in PL with epidemiological characteristics that contrast with those of the developed world. This retrospective study analysed 52 cases of PL at Chris Hani Baragwanath Academic Hospital (CHBAH), National Health Laboratory Service (NHLS), during the time period from 1 January 2007 to 1 June 2013. The epidemiological and pathological data analysed includes the HIV status, gender, age, site of biopsy at disease presentation, histopathological subtypes, stage of disease at presentation, the presence or absence of opportunistic infections and the use of highly active antiretroviral therapy. The prognostic significance of these data parameters was investigated, together with the survival outcomes of the different histopathological subtypes. Of the 52 PL cases analysed, there were 27 (52%) cases of non-Hodgkin lymphoma (NHL) and 25 (48%) cases of classical Hodgkin lymphoma (CHL). Seventeen (33%)patients were HIV seropositive and 35 (67%) were HIV seronegative. NHL was significantly more prevalent in the HIV seropositive group while CHL was more prevalent in the HIV seronegative group (p = 0.0003). The commonest histopathological NHL subtype was BL (44%), which occurred predominantly in the HIV seropositive group (p=0.03). Of note are some unusual cases of NHL, which included 3 cases of plasmablastic lymphoma (PBL), 2 cases of B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBL) and BL and 1 case of T cell/histiocyte rich B-cell lymphoma (THRLBCL). The commonest CHL subtype was nodular sclerosis (40%). The overall male to female ratio was 4.2:1. The overall mean age of the PL cohort was 7.5 years (standard deviation [SD]: 3.5 years), while the mean ages of the NHL cohort and CHL cohort were 7 years (SD: 4 years) and 8 years (SD: 2.8 years) respectively. Lymphoma presentation occurred at a significantly older age in the HIV seropositive NHL group ( mean age of 8.6 years [SD: 3.8] ; median age of 9 years [IQR: 7; ) than the HIV seronegative NHL group (mean age of 5.1 years [SD: 3.5]; median age of 4 years [IQR: 5]; p = 0.03). A conspicuous prevalence of extranodal disease at presentation was found in cases of NHL (92.6%). In the CHL group, the topographic sites of involvement were relatively evenly distributed between nodal (52%) and extranodal regions (48%). Statistical analysis revealed a significantly higher mortality in patients afflicted with NHL (66.7%) compared to CHL (24%) (p = 0.003). No significant influence on survival was demonstrated when assessing the stage of disease in the NHL (p = 0.59) and CHL groups (p = 0.6), nodal versus extranodal topography in CHL (p = 0.14) and the presence of opportunistic infections (p = 0.3). The important findings of this study were the similar survival outcomes of patients in the HIV seropositive and seronegative groups who had NHL and specifically BL. Highly active antiretroviral therapy (HAART) together with chemotherapy administration has improved the prognosis of HIV seropositive PL patients. / MT2017

Implementation of international guidelines for the treatment of epileptic spasms, is challenging when access to adrenocorticotrophic hormone (ACTH) and vigabatrin is restricted, especially in Low and Middle Income Countries (LMIC). Oral corticosteroids are alternative interventions but evidence for the optimal agent, dose, duration, efficacy and long-term effects are lacking. A systematic review of the literature was performed to assess the quality of evidence of prednisone and prednisolone (oral corticosteroids) for the management of epileptic spasms. There is level C recommendation based on class III evidence to support the efficacy of oral corticosteroids for the acute clinical control of epileptic spasms and EEG resolution. Efficacy of oral corticosteroids in comparison to the internationally recommended intervention of ACTH has class IV evidence supporting level U recommendation. Similarly, there is no data on the risk of relapse with oral corticosteroids (class IV, level U), compared to ACTH. There is class IV evidence supporting level U recommendation for the safety of oral corticosteroids and class II evidence for level B recommendation for ACTH. In terms of oral corticosteroids and effects on long-term development there is class IV evidence leading to level U recommendation, compared to class III evidence supporting level C recommendation for ACTH. Randomized controlled studies are needed to compare oral corticosteroids with ACTH, the optimal dosage and regimen as well as the long-term neurodevelopmental outcomes. Based on the limited existing studies a treatment guideline for LMIC is proposed which could be used to standardize interventions permitting clarification of these unmet questions.

Background: Laboratory biomarkers are important adjuncts to clinical data in diagnosing neonatal sepsis. Available diagnostic tests often provide results 6 to 48 hours later. A bedside C-reactive protein (CRP) test may be able to exclude or diagnose sepsis within minutes. Objectives: The objectives were to validate the Alere AfinionTM point of care test (POCT) CRP in a tertiary neonatal unit against the gold standard CRP assay in use by the National Health Laboratory service and to determine the difference in time to obtaining a result between the two systems. Methods: A prospective observational study was conducted between February 2015 and June 2015. Neonates who were clinically indicated to undergo CRP testing were simultaneously tested using the POCT and laboratory assays. The sensitivities, specificities and predictive values for the POCT, with the laboratory test as the reference test were determined. The time to results between the two tests was compared. Results: There were 139 measured CRP sample pairs from patients with suspected or proven neonatal sepsis. Using 10 mg/L as the cutoff value for both CRP tests, the sensitivity, specificity, positive predictive value and negative predictive value were 97.4%, 99%, 97.4% and 99% respectively. The area under the receiver operating characteristic curve was 0.99 (p<0.001). The time to point of care result was 4 minutes. Laboratory results were registered at a mean of 4.7 hours but only checked after a mean of 6.8 hours. Conclusions: The POCT CRP and laboratory CRP test have excellent correlation in neonates and may be a useful, quick, reliable method to rationalise antibiotic usage, reduce costs and allow for earlier patient discharge.

Background: Due to the poor outcomes achieved in acute myeloid leukaemia (AML) treatment, the Red Cross War Memorial Children's Hospital (RCWMCH) Oncology service changed from a BFM-87 based protocol to one based on MRC-AML15 in 2007. Rationale: This study was designed to assess the outcomes and treatment - related toxicity among children treated with RCWMCH protocol Rx 2071. Methods: This was a retrospective review of AML patients treated with Rx2071 between 2007 and 2012 at RCWMCH. Patients with acute promyelocytic leukaemia (APL) and Down Syndrome were excluded. Risk was assigned by cytogenetics. Good risk patients were those with t(8;21), t(16,16) and inv(16). Poor and standard risk included all other cytogenetics according to MRC-AML15. Data pertaining to toxicity was obtained from patient folders. Results: Thirty five children were treated on Rx 2071 during the study period. Males comprised 51.4% (18/35) and females 48.6% (17/35). Age at diagnosis ranged from 0.33 to 12.51 years with the median being 5.68 years. Follow-up from remission in the patients who survived ranged from 1 year 10 months to 9 years 1 month with a median of 62.5 months. Fifteen patients had favourable cytogenetics. Event free survival (EFS) for the good risk group was 85.6%. Twenty patients presented with standard/poor risk cytogenetics. Five patients were deemed poor risk with one having major karyotype abnormalities and four not achieving remission. The remaining fifteen were deemed standard risk by cytogenetics. EFS in this group was 32.4%. Two standard/poor risk patients were transplanted in first complete remission (CR1) and two patients were transplanted in second complete remission. (CR2) Patients had a median of four neutropaenic fevers, and required a median of eight packed cell and eleven platelet transfusions. There were 39 positive blood cultures. There were no chemotherapy related deaths. Discussion: The EFS for good risk patients is excellent but the EFS for standard/poor risk group is not on par with results being achieved in high income countries. The toxicity is not excessive on Rx2071. The results achieved on this protocol were superior to that of the previous BFM- based protocol. Conclusion: The results of this study support the continued use of Rx2071 at RCWMCH.

Acute liver failure (ALF) describes a clinical syndrome resulting from severe liver damage and extensive loss of functional parenchymal liver mass triggered by various factors. Early recognition and initiation of specific therapy may improve outcomes and reduce the need for liver transplantation, a treatment modality not universally available in resource constraint areas. There is paucity of data describing this syndrome in Sub-Saharan Africa in children. Objective This study aims to retrospectively review and determine the clinical presentation, aetiology, complications &amp; outcome of ALF in children admitted at the Red Cross War Memorial Children's Hospital (RCWMCH). Methods All records of children from 0 to 13 years admitted at the RCWMCH over the period from January 2005 to December 2016 with ALF were retrospectively reviewed, after obtaining ethical approval. Patients with pre-existing evidence of chronic liver disease were excluded. Demographic variables as well as clinical presentation and investigations were captured, with determination of outcomes at 3 weeks and 6 weeks of diagnosis. Results Study included 24 children., 16 females (66.7%) and 8 males (33.3%). Median Age was 15 months, with interquartile range from 5 to 28 months. Diarrhoea, jaundice, respiratory distress, hepatomegaly and encephalopathy were common clinical features. Aetiology was infection in 37.5 % of cases (n=9, 2 of whom had autoimmune hepatitis comorbidity) and hepatitis A was most common infectious cause (n=4, 44%). Causes were indeterminate in 29.2%. Two patients had autoimmune hepatitis without co-morbidity; Reye syndrome 12.5% and 17% had miscellaneous causes. Transaminases were raised to thousands in viral causes of hepatitis, with a low C reactive protein. INR >4 and Total Bilirubin>210umol/L were associated with death outcome (p=0.04 and p=0.03 respectively. Conclusion Viral hepatitis A is the leading infective cause of acute liver failure in this study cohort and 29.2% of cases were indeterminable. INR >4 and Bilirubin > 210umol/l were predictors of poor outcome. Follow up study is recommended to better understand clinical spectrum and outcomes of children with acute liver failure in this low resource setting.

Background: The majority of central nervous system tumours in children are low grade gliomas (LGG). Long-term survival rates are high with a slow, progressive course. Tumour location and extent of resection affect outcome. Adjuvant therapy has an important role. Rationale: This study evaluated the demographic data of our patient population, the characteristics of LGGs in our setting, the time to presentation, and the role of adjuvant therapy including more targeted, novel biologic therapy such as BRAF/MEK inhibitors. The outcome of children with LGGs in our institution was assessed. Methods: A retrospective analysis was performed on all children < 15 years of age diagnosed with a LGG at Red Cross War Memorial Children's Hospital (RCWMCH) between 2001 and 2017. Data were collected from patient hospital folders, as well as paediatric oncology records and Groote Schuur Hospital radiotherapy records. Results: Eighty-six children aged 0.10-13.76 years (median 4.74 years) were diagnosed with LGGs between 2001 and 2017 at RCWMCH. Median time to presentation was 60 days. Sixtyfive patients (76%) were classified as having a WHO Grade I and 21 patients WHO Grade II (24%) tumours. Five patients (6%) had metastatic disease at presentation. The most common sites involved were the cerebellum (27%), hypothalamus (17%) and cerebrum (14%). The most common histology was juvenile pilocytic astrocytoma (JPA) (n=62; 73%). Gross total resection (GTR) was achieved in 21 patients (24%). Twenty-four patients (27%) received chemotherapy of which 11 patients progressed. Twenty-two patients received radiotherapy (26%), of which 3 patients progressed. The estimated 5-year overall survival (OS) was 86.8% and the estimated 5-year progression free survival (PFS) was 42.8%. The presence of a BRAFV600E mutation was checked in 4 patients since 2013, all had JPA histology, and all were negative. Discussion: Our patient demographic differed from published data with respect to younger age at presentation and female predominance. Time to presentation was relatively short. The majority of LGGs were cerebellar, with JPA histology being the most common. GTR was achieved in almost a quarter of patients. WHO Grade II histology did not significantly impact PFS and OS. Children < 3 years had a lower PFS compared to children > 3 years, but OS was similar. OS in this study was comparable to published data in developed countries, however PFS was slightly lower. Conclusion: Our outcomes are similar to those achieved in developed countries. Chemotherapy and radiotherapy are valuable adjuncts to treatment. The presence of a BRAF alterations should be tested in recurrent/progressive disease, to guide use of novel treatments.

Includes abstract. / Includes bibliographical references (leaves 64-72). / Posterior urethral valve (PUV) is a congenital obstructing membrane of the male urethra. It is the commonest cause of bladder outlet obstruction in male children. PUV as a cause of obstructive uropathy is an important cause of end stage renal failure (ESRF) in children. Early detection and surgical intervention can slow down progression to ESRF.

Includes abstract. Includes bibliographical references.

Background Uveitis is a known cause of blindness in the developed world, where non-infectious diseases dominate the spectrum of underlying aetiologies. However, data from sub-Saharan Africa is lacking. Here we aim to describe the diseases associated with non-infectious uveitis and the impact of currently available treatment in this setting. Methods A retrospective observational analysis of children with non-infectious uveitis from January 2010 to December 2017, attending the tertiary paediatric rheumatology and ophthalmology referral units in Cape Town was conducted. Statistical analysis utilising STATA13 software was performed with p < 0.05 considered significant. Results Twenty-nine children were identified with a median age at first visit of 74 months (IQR 49–86 months), female to male ratio of 0.9:1, predominantly of mixed race (72.4%). Juvenile idiopathic arthritis associated uveitis (JIAU) (48.3%) was the most frequent diagnosis. All children with JIAU had chronic anterior uveitis and 3 (21.4%) presented with uveitis before arthritis. There were no differences between children with uveitis and those with arthritis only, for gender (p = 0.68) and race (p = 0.58) but significantly, children with uveitis presented at an overall younger age (p = 0.008), with antinuclear antibody positive (p < 0.001) oligo-articular JIA (p = 0.01) and older age appeared to be protective (p = 0.01 OR1.0 CI 0.6-1.7). Children with idiopathic uveitis (41.4%) were predominantly male (66.6%), of mixed race (75%), with chronic anterior uveitis (41.7%) and presented with cataracts (100%). Less commonly, sarcoidosis (6.9%) and Behcet's disease (3.5%) were diagnosed. 55.2% had complications at presentation, predominantly cataracts (87.5%). 19 children (65.5%) had inactive disease at 12 months from diagnosis and remission as assessed at the last clinical visit, was achieved in 58.6% on standard initial therapy and in 75% of those on tumour necrosis factor inhibitors. Surgery was needed in 41.4%, primarily in the idiopathic group. Visual acuity improved or was maintained on treatment. Conclusion The spectrum and characteristics of immune mediated non-infectious uveitis are comparable to that reported in developed countries. Current practice detects children with potentially sight-threatening disease and access to tumour necrosis factor inhibitors has improved outcomes in refractory cases.

Introduction Infective endocarditis is a microbial infection of the endothelial surface of the heart, predominantly the heart valves, that is associated with high mortality and morbidity. Few contemporary data exist regarding affected children in our context. Aims and Objectives: We aimed to describe the profile and treatment outcomes of infant and childhood endocarditis at our facilities. Methods: This is a retrospective review of infants and children with endocarditis at two public-sector hospitals in the Western Cape Province of South Africa over a 5-year period. Patients with “definite” and “possible” endocarditis according to Modified Duke Criteria were included in the review. Results: Forty-nine patients were identified for inclusion; 64% of patients met “definite” and 36% “possible” criteria. The in-hospital mortality rate was 20%; 53% of patients underwent surgery with a post-operative mortality rate of 7.7%. The median interval from diagnosis to surgery was 20 days (interquartile range 9-47 days). Valve replacement occurred in 28% and valve repair in 58%. There was a significant reduction in valvular dysfunction in patients undergoing surgery and only a marginal improvement in patients treated medically. Overall, 43% of patients had some degree of residual valvular dysfunction. Conclusion: Endocarditis is a serious disease with a high in-hospital mortality and presents challenges in making an accurate diagnosis. Despite a significant reduction in valvular dysfunction, a portion of patients had residual valvular dysfunction. Early surgery is associated with a lower mortality rate, but a higher rate of valve replacement when compared to delayed surgery.