Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007-2021).

BACKGROUND: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age < 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. METHODS: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. RESULTS: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007-08/02/2021) and DN Surveillance (2010-2013) was 70% and 69% respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92% and 84% respectively between RHIS and Child PIP, and 98% and 83% respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95% CI: 1.37-1.85) to 0.73 (95% CI: 0.56-0.93) deaths per 1000 live births from 2007 to 2020. CONCLUSION: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.

Using ceftazidime-avibactam for persistent carbapenem-resistant Serratia marcescens infection highlights antimicrobial stewardship challenges with new beta-lactam-inhibitor combination antibiotics.

The newer beta-lactam-inhibitor combination (BLIC) antibiotics are available in South Africa (SA) for the treatment of carbapenem-resistant Enterobacterales infections. We describe the successful use of ceftazidime-avibactam (CA) for the treatment of a child with persistent carbapenem-resistant Serratia marcescens bacteraemia, and the challenges faced using this lifesaving antibiotic, including access to susceptibility testing, procurement process, cost and complexity of deciding when, how and for how long to use it. Furthermore, the burden of carbapenem resistance is increasing in SA, and inappropriate use of CA and other newer BLIC antibiotics, such as ceftolozane-tazobactam, will inevitably endanger their longevity. A careful balance must be struck between removing unnecessary obstacles and delays in initiating these antibiotics for life-threatening infections, and additional antimicrobial stewardship-guided interventions aimed at preserving their therapeutic use.

Association between Gc genotype and susceptibility to TB is dependent on vitamin D status.

Group-specific component (Gc) variants of vitamin D binding protein differ in their affinity for vitamin D metabolites that modulate antimycobacterial immunity. We conducted studies to determine whether Gc genotype associates with susceptibility to tuberculosis (TB). The following subjects were recruited into case-control studies: in the UK, 123 adult TB patients and 140 controls, all of Gujarati Asian ethnic origin; in Brazil, 130 adult TB patients and 78 controls; and in South Africa, 281 children with TB and 182 controls. Gc genotypes were determined and their frequency was compared between cases versus controls. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were obtained retrospectively for 139 Gujarati Asians, and case-control analysis was stratified by vitamin D status. Interferon (IFN)-gamma release assays were also performed on 36 Gujarati Asian TB contacts. The Gc2/2 genotype was strongly associated with susceptibility to active TB in Gujarati Asians, compared with Gc1/1 genotype (OR 2.81, 95% CI 1.19-6.66; p = 0.009). This association was preserved if serum 25(OH)D was <20 nmol.L(-1) (p = 0.01) but not if serum 25(OH)D was > or =20 nmol.L(-1) (p = 0.36). Carriage of the Gc2 allele was associated with increased PPD of tuberculin-stimulated IFN-gamma release in Gujarati Asian TB contacts (p = 0.02). No association between Gc genotype and susceptibility to TB was observed in other ethnic groups studied.

A retrospective description of primary immuno-deficiency diseases at Red Cross War Memorial Children's Hospital, Cape Town, South Africa, 1975 - 2017.

BACKGROUND: The primary immunodeficiency diseases (PIDs) constitute a diverse and ever-expanding group of inborn errors affecting a wide range of immune functions. They are not well documented in sub-Saharan Africa. OBJECTIVES: To describe the spectrum of PIDs at a tertiary paediatric hospital. METHODS: A retrospective descriptive study of PIDs diagnosed at Red Cross War Memorial Children's Hospital, Cape Town, South Africa (SA), between 1975 and 2017 was undertaken. RESULTS: We identified 252 children with PIDs, spanning eight of the nine categories listed in the 2017 classification of the International Union of Immunological Societies. Predominantly antibody deficiencies, combined immunodeficiencies with associated syndromic features, and immunodeficiencies affecting cellular and humoral immunity accounted for most children with PIDs (n=199, 79.0%). The mean age (standard deviation) at diagnosis was 46 (50) months, and the male/female ratio was 1.5:1. There was a history of parental consanguinity in 3 cases (1.2%). Recurrent infection was the most prevalent presenting phenotype, manifesting in 177 patients (70.2%). Genetic or chromosomal confirmation was obtained in 42/252 cases (16.7%). Common interventions used to prevent infection were antimicrobial prophylaxis and immunoglobulin replacement therapy, administered to 95 (37.7%) and 93 (36.9%) of the patients, respectively. Six of 7 children who underwent haematopoietic stem cell transplantation (HSCT) had successful outcomes. The 7th patient died 2 months after HSCT from overwhelming infection. Although we could not account for the children lost to follow-up during the study period, 53 deaths were confirmed (21.0%). CONCLUSIONS: Several challenges exist in the recognition and treatment of children with PIDs in our setting. These include limited access to genetic diagnostics and HSCT. Suboptimal treatment options contribute to the overall mortality of PIDs in SA.

High incidence of tuberculosis among HIV-infected infants: evidence from a South African population-based study highlights the need for improved tuberculosis control strategies.

BACKGROUND: There are limited population-based estimates of tuberculosis incidence among human immunodeficiency virus (HIV)-infected and HIV-uninfected infants aged < or =12 months. We aimed to estimate the population-based incidence of culture-confirmed tuberculosis among HIV-infected and HIV-uninfected infants in the Western Cape Province, South Africa. METHODS: The incidences of pulmonary, extrapulmonary, and disseminated tuberculosis were estimated over a 3-year period (2004-2006) with use of prospective representative hospital surveillance data of the annual number of culture-confirmed tuberculosis cases among infants. The total number of HIV-infected and HIV-uninfected infants was calculated using population-based estimates of the total number of live infants and the annual maternal HIV prevalence and vertical HIV transmission rates. RESULTS: There were 245 infants with culture-confirmed tuberculosis. The overall incidences of tuberculosis were 1596 cases per 100,000 population among HIV-infected infants (95% confidence interval [CI], 1151-2132 cases per 100,000 population) and 65.9 cases per 100,000 population among HIV-uninfected infants (95% CI, 56-75 cases per 100,000 population). The relative risk of culture-confirmed tuberculosis among HIV-infected infants was 24.2 (95% CI, 17-34). The incidences of disseminated tuberculosis were 240.9 cases per 100,000 population (95% CI, 89-433 cases per 100,000 population) among HIV-infected infants and 14.1 cases per 100,000 population (95% CI, 10-18 cases per 100,000 population) among HIV-uninfected infants (relative risk, 17.1; 95% CI, 6-34). CONCLUSIONS: This study indicates the magnitude of the tuberculosis disease burden among HIV-infected infants and provides population-based comparative incidence rates of tuberculosis among HIV-infected infants. This high risk of tuberculosis among HIV-infected infants is of great concern and may be attributable to an increased risk of tuberculosis exposure, increased immune-mediated tuberculosis susceptibility, and/or possible limited protective effect of bacille Calmette-Guérin vaccination. Improved tuberculosis control strategies, including maternal tuberculosis screening, contact tracing of tuberculosis-exposed infants coupled with preventive chemotherapy, and effective vaccine strategies, are needed for infants in settings where HIV infection and tuberculosis are highly endemic.

Disseminated bacille Calmette-Guérin disease in HIV-infected South African infants.

OBJECTIVE: To determine the population-based incidence of disseminated bacille Calmette-Guérin (BCG) disease in HIV-infected infants (aged

Short-term outcomes of down-referral in provision of paediatric antiretroviral therapy at Red Cross War Memorial Children's Hospital, Cape Town, South Africa: A retrospective cohort study.

BACKGROUND: The large scale-up of paediatric HIV care necessitated down-referral of many children receiving antiretroviral therapy (ART) from Red Cross War Memorial Children's Hospital (RCWMCH), Cape Town, South Africa. Few published data exist on the outcomes of these children. OBJECTIVES: To assess outcomes of children receiving ART in the first 12 months after down-referral to primary healthcare (PHC) clinics and identify determinants of successful down-referral. METHODS: A retrospective cohort study of children <15 years of age who initiated ART at RCWMCH and were subsequently down-referred to one of two PHC clinics between January 2006 and December 2012 was completed. Baseline characteristics of patients and caregivers as well as CD4+ counts, viral loads (VLs) and weights were collected 6 and 12 months after down-referral. Outcomes included retention in care and viral suppression. RESULTS: Of 116 children down-referred to the two study PHC clinics, 81.9% arrived at the designated PHC clinic and a further 8.6% continued care at other clinics, the remaining 9.5% being lost to follow-up. Of those successfully down-referred, 11.4% took >8 weeks to present, possibly experiencing treatment interruption. At 12 months after down-referral, only 81.0% remained in care. No factors were associated with retention in care in multivariable analysis. For children who remained in care at the designated PHC clinics, the clinical and immunological gains achieved prior to down-referral were sustained through 12 months of follow-up, and 54.7% of this cohort had documented viral suppression at 12 months. However, if only children with VL results are considered, 75.9% (41/54) were virally suppressed 12 months after down-referral. CONCLUSIONS: Down-referral of children on ART is complex, with risk of loss to follow-up and treatment interruption.

Fulminant hepatitis B virus (HBV) infection in an infant following mother-to-child transmission of an e-minus HBV mutant: Time to relook at HBV prophylaxis in South African infants.

The prevalence of hepatitis B virus (HBV) infection in pregnant women is high in South Africa (SA), yet prophylaxis to prevent mother-to-child transmission (MTCT) falls short of international recommendations. We describe a 10-week-old infant who developed fulminant hepatic failure following MTCT. The mother was hepatitis e-antibody positive and had a viral load of only 760 IU/mL. Genetic analysis of virus from mother and infant showed that both had the G1896A mutation in the preC/C gene, which truncates hepatitis e antigen (HBeAg) during translation, causing an HBeAg-negative phenotype. HBeAg attenuates antiviral immune responses, and its absence was probably responsible for the infant's fulminant hepatitis, due to an uncontrolled immune attack on infected liver cells. Pregnant women are not tested for HBV infection in SA and MTCT rates are unknown. Addition of a birth dose of vaccine, HBV screening of pregnant women and antiviral prophylaxis to positive mothers should be prioritised.

Tuberculosis during early antiretroviral-induced immune reconstitution in HIV-infected children.

SETTING: Referral paediatric hospital, Cape Town, South Africa. OBJECTIVE: To describe the clinical manifestations of Mycobacterium tuberculosis (TB) associated disease in human immunodeficiency virus (HIV) infected children during early antiretroviral-induced immune reconstitution. DESIGN: Case series. RESULTS: Eleven patients with probable or culture confirmed TB were identified. Seven presented after a median 25 (range 8-54) days on highly active antiretroviral therapy (HAART) with pulmonary TB and one also had extra-pulmonary disease. Three of the patients had a prior history of TB and presented with relapse or recurrent disease. Four patients with TB developed a tuberculous paradoxical reaction; one died of suspected tuberculous immune reconstitution pneumonitis. The duration of pre-HAART anti-tuberculosis treatment and antiretroviral treatment ranged from 21 to 59 and 6 to 105 days, respectively, when they presented with a paradoxical reaction. Drug-resistant (isoniazid and rifampicin) TB was cultured from one patient with relapse disease. Chest radiograph features present during immune reconstitution were increasing or new intrathoracic lymphadenopathy, parenchymal infiltrates and pleural effusions. CONCLUSION: This report documents the clinical presentation of TB during the early phase of HAART which may be attributed to HAART-mediated immune reconstitution. More research is needed to improve the accuracy of TB diagnosis in HIV-infected children.

Contextualising the paediatric HIV epidemic: a review.

OBJECTIVE: To draw attention to the sub-optimal care that HIV-infected children are receiving in Africa. DATA SOURCES: Relevant published literature. DATA SYNTHESIS: Sub-optimal response to paediatric HIV infection has aggravated the negative impact that the epidemic has had on child health in Africa. Recently the African Network for the Care of Children Affected by HIV/AIDS (ANNECA) released an advocacy statement that called for the optimisation of prevention, diagnosis, treatment and care for children affected by the AIDS pandemic. Effective prevention strategies if comprehensively implemented, could prevent more than 500 000 paediatric infections per annum at current antenatal HIV prevalence rates. Improved care that includes universal utilisation of early diagnostic testing systems, cotrimoxazole prophylaxis, nutritional support and the timely introduction of antiretroviral therapy could improve the quality of life and lifespan of most infected children. CONCLUSION: Political leaders, public health officials and fellow child health professionals are urged to redouble their efforts to reverse the magnitude of the paediatric epidemic in Africa.

Enzyme-linked immunospot assay responses to early secretory antigenic target 6, culture filtrate protein 10, and purified protein derivative among children with tuberculosis: implications for diagnosis and monitoring of therapy.

BACKGROUND: The ability to detect tuberculosis-specific lymphocytes by enzyme-linked immunospot (ELISPOT) assay may have important implications for the diagnosis and monitoring of tuberculosis in children, for which routine methods lack sensitivity. We conducted a study to determine the presence and time course of ELISPOT responses in children with tuberculosis. METHODS: Blood samples were obtained from children with a clinical diagnosis of tuberculosis, and interferon-gamma ELISPOT assays were performed using purified protein derivative (PPD), early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP10) as stimulants. A subset of children were retested after 1, 3, and 6 months of therapy. RESULTS: Detectable responses to ESAT-6 or CFP10 were found in 49 of 70 children with clinical tuberculosis but were more frequently found in those with culture-proven disease (P = .05). The number of subjects with responses to PPD increased after 1 month of therapy (P = .0004) and decreased at 3 and 6 months. CONCLUSION: Tuberculosis-specific ELISPOT testing is a promising tool that should be evaluated as a potential diagnostic test for childhood tuberculosis. We caution against the use of an early decrease in response as a marker of successful antituberculous chemotherapy.

Short-term treatment outcomes of children starting antiretroviral therapy in the intensive care unit, general medical wards and outpatient HIV clinics at Red Cross War Memorial Children's Hospital, Cape Town, South Africa: A retrospective cohort study.

BACKGROUND: Many HIV-infected children are initiated on antiretroviral therapy (ART) during hospitalisation in South Africa (SA). No published data on these outcomes exist. OBJECTIVES: To assess the short-term outcomes of children initiated on ART in the intensive care unit (ICU), general medical wards (GMWs) and outpatient HIV clinics (OHCs) at Red Cross War Memorial Children's Hospital (RCWMCH), Cape Town, SA. METHODS: We conducted a retrospective cohort study of HIV-infected children aged <13 years commenced on first-line ART between January 2008 and December 2011. Outcomes included death, virological suppression and changes in CD4 count. Kaplan-Meier estimates, multivariate Cox proportional hazard ratios and logistic regression were used to estimate outcomes at 6 months. RESULTS: One hundred and six children were commenced on ART in the ICU, 509 in the GMWs and 127 in the OHCs; 65.7% of all children were <12 months old. Of children qualifying for rapid ART initiation according to the 2013 national treatment guidelines, 182 (24.9%) started therapy within 7 days of diagnosis. Overall mortality was 6.4% (95% confidence interval (CI) 4.9 - 8.4). Of children remaining in care at RCWMCH, 51.0% achieved a CD4 percentage ≥25% and 62.3% a viral load ≤50 copies/mL 6 months after ART initiation. Mortality was higher in the ICU cohort (13.2%) than in the GMW and OHC cohorts (5.5% and 3.9%, respectively, log-rank p=0.004). Predictors of mortality included moderate underweight (adjusted hazard ratio (aHR) 2.4; 95% CI 1.1 - 5.2), severe underweight (aHR 3.2; 95% CI 1.6 - 6.5), absence of caregiver counselling sessions (aHR 2.9; 95% CI 1.4 - 6.0) and ART initiation in the ICU (aHR 2.6; 95% CI 1.4 - 4.9). CONCLUSION: These results highlight the importance of understanding the context in which children initiate ART, when comparing outcomes in different settings.

False-negative HIV-1 polymerase chain reaction in a 15-month-old boy with HIV-1 subtype C infection.

Polymerase chain reaction (PCR) testing is the gold standard for determining the HIV status in children <18 months of age. However, when clinical manifestations are not consistent with laboratory results, additional investigation is required. We report a 15-month-old HIV-exposed boy referred to our hospital after he had been admitted several times for infectious diseases. A rapid antibody test on the child was positive, while routine diagnostic HIV PCRs using the Roche COBAS Ampliprep/COBAS TaqMan HIV Qual Test were negative at 6 weeks, 6 months, 7 months and 15 months. In addition, the same PCR test performed on the HIV-infected mother was also negative. Alternative PCR and viral load assays using different primer sets detected HIV RNA or proviral DNA in both child and mother. Gag sequences from the child and his mother classified both infections as HIV-1 subtype C, with very rare mutations that may have resulted in PCR assay primer/probe mismatch. Consequently, the child was commenced on antiretroviral therapy and made a remarkable recovery. These findings indicate that more reliable PCR assays capable of detecting a wide range of HIV subtypes are desirable to circumvent the clinical problems created by false-negative PCR results.

The effect of chronic low level lead exposure on blood-brain barrier function in the developing rat.

Blood-brain barrier (BBB) function was assessed in 19-21-day-old rats exposed to low level lead from birth. Newborn rats received lead via milk from lactating dams given drinking water containing 0.1% lead acetate [Pb(Ac)2]. The treatment regime produced lead levels in the neonates within the range 20-80 micrograms dl-1 blood, without affecting growth. Cerebrovascular permeability (PS-product) to the diffusion-limited solute mannitol was unchanged in six regions of the cerebral hemisphere, the cerebellum and the brainstem, suggesting that barrier integrity was not affected by the low dose lead treatment. Regional cerebrovascular permeability to nutrient tracers representing seven BBB transport classes was not impaired by lead treatment. However, the PS estimates for the amino acids lysine and histidine and for thiamine were greater than control in some regions of the cerebral hemisphere. These alterations in nutrient supply to the brain may reflect altered substrate utilization associated with repair processes or delayed maturation of the CNS.

Influence of a standard laboratory diet containing nutritionally adequate levels of selenium on renal pathology from mercury released by experimental amalgam tattoos.

Twenty-four guinea pigs were subcutaneously implanted with 2 X 25 mg of powdered dental amalgam for between 1 and 24 months. Four animals served as controls. All animals were fed a standard diet containing 0.2 microgram/g selenium (Se). Mercury (Hg) was released from the implants at an average rate of 21.7 micrograms/d and 4.35-16.94 micrograms of Se were consumed daily in the diet. The renal Hg rose to a maximum of 263 micrograms/g at 11 months in implanted animals and 6.65 mg Hg was excreted over 2 yr. The renal proximal tubular cells of implanted animals contained visible Hg deposits in secondary lysosomes and within nuclei containing both Hg and Se. No other signs of obvious renal pathology were seen in implanted animals as compared with controls. It would seem likely that the low Se levels present within this standard laboratory diet were sufficient to protect against Hg toxicity.

Tissue reactions to the separate implantation of individual constituent phases of dental amalgam, including assessment by energy dispersive X-ray microanalysis.

Soft tissue degradation of the 3 principal amalgam phases have been investigated in relation to their role in the formation of the amalgam tattoo. Each phase, finely powdered, was implanted subcutaneously into the submandibular region of guinea-pigs for periods ranging from 1 week to 1 year. The rates of breakdown were assessed radiographically and the final lesions were examined by light and electron microscopy and X-ray microanalysis. gamma 2 (Sn7Hg) phase degraded rapidly, mainly extracellularly, and did not produce a tattoo. Both mercury and tin disappeared from the lesion. gamma 1 (Ag2Hg3) phase degraded less rapidly, both extra and intracellularly, and produced a small tattoo. Mercury was lost from the lesion. gamma (Ag3Sn) phase degraded slowly, intracellularly, and produced a large tattoo. Tattoos always resulted from persistence of minute particles of silver and sulphur associated with basal lamina and connective tissue.

Renal cortical mercury levels associated with experimental amalgam tattoos: effects of particle size and amount of implanted material.

Powdered dental amalgam that had passed through either a 106 microns or a 45 microns sieve was implanted subcutaneously in guinea pigs for periods of up to 2 yr. The renal cortical mercury levels associated with the 106 microns material were on average 16% of those produced by the 45 microns material. A reduction in the amount of 45 microns powder implanted, by a factor of 75%, resulted in a fall of only 27% in renal mercury concentrations. The marked effect of particle size on mercury release may be explained by the large increase in the proportion of implanted material that was degraded within phagocytic cells in the local lesions.

Further investigations of the soft tissue reaction to the gamma 1 phase (Ag2Hg3) of dental amalgam, including measurements of mercury release and redistribution.

The subcutaneous implantation in guinea pigs of powdered gamma 1 phase induced a severe initial tissue response and the majority of the material was extruded from the healing wounds. This process was accompanied by the release of significant amounts of mercury which appeared in the body organs and excreta. The small numbers of particles which remained in the tissues were handled quite differently, undergoing slow degradation in macrophages and giant cells in chronic granulomata. Minute secondary particles containing silver and sulphur were deposited in the tissues and gave rise to macroscopic tattooing of the skin above the implants.

Further investigations of the soft tissue reaction to the gamma 2 phase (Sn7-8Hg) of dental amalgam, including measurements of mercury release and redistribution.

Following the subcutaneous implantation in guinea pigs of powdered gamma 2 phase with a mercury content only slightly greater than that indicated by the stoichiometric formula Sn7Hg, there was a limited initial release of mercury from extracellular material. Thereafter, chronic granulomata developed around the implants and particles degraded slowly in macrophages and giant cells. Vast numbers of fine secondary particles containing tin were produced and these were associated with macroscopic staining. Mercury seemed to be lost as the result of intracellular particle breakdown but it did not accumulate in the body organs or appear to any great extent in the excreta.

The fate of amalgam implanted in soft tissues -- an experimental study.

The soft tissue reaction to amalgam depended on whether it was finely ground or a solid mass. Finely ground amalgam was actively digested within macrophages and giant-cells with loss of mercury and the formation of the fine particles of silver and sulphur. Larger masses became surrounded by a fibrous capsule.