Paediatrics and Child Health

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Assisted respiration in the treatment of neonatal tetanus.
(1967) Thambiran, A. K.
The oxygen consumption in tetanus neonatorum.
(1968) Desai, S. D.; Adams, E. B.; Ripley, S. H.
No abstract available.
Host allergic response variation in children with measles infection.
(1977) Coovadia, Hoosen Mahomed.; Smythe, P. M.
In many infections some patients recover while others die or are permanently disabled. These extremes in clinical outcome may be determined as much by the capacity of the host to eliminate the infecting agent as by the antigenic load on the individual. Children with measles who do not recover may succumb to acute complications (mainly respiratory) or chronic disease (respiratory and neurological) may develop. Analysis of immunological function antedating any of these final events would assist in understanding their pathogenesis and possibly aid in management. In order to achieve t h i s , immunological responsiveness was at f i r st studied in 24 children with acute measles and compared with that in 20 children with established chronic post measles chest disease investigated 6 - 1 6 weeks after appearance of the rash. The immunosuppressive effects of acute measles were extensive. Total white cells were reduced and this reduction was accounted for entirely by lymphopenia which was equally expressed among the major lymphocyte sub-populations studied; the function of T cells, assessed by radioisotope incorporation into phytohaemaggiutinin-transformed lymphocytes and by delayed skin hypersensitivity to dinitrochlorobenzene, was depressed. Serum IgA was reduced in acute measles patients. In contrast there was a relative sparing of the measured indices of immunity in patients with chronic post measles chest disease, with the major defect being an impaired delayed hypersensitivity reaction to dinitrochlorobenzene. There were minor alterations in complement components in both groups of patients with the evidence suggesting minimal utilisation of the alternative pathway in acute measles and classical pathway in chronic patients. High levels of heterophile antibodies to sheep red blood cells were detected in patients with chronic chest disease. (11) The results suggested that the conditions for chronicity of pulmonary disease in measles were unlikely to be determined by persistent abnormalities in the immunopathological factors enumerated, most of which were normal in chronic patients. It was not possible to interpret the findings of defective delayed hypersensitivity and complement components in patients with chronic chest disease as being either the cause or the effect of chronicity. The latter findings would have to be compared with results in children who had recovered from measles studied six weeks after onset of rash. An attempt was made to resolve this problem. Twenty-two children with measles were studied in the acute stage of the rash and six weeks later and results compared with matched controls. The above findings in acute measles were confirmed: the total lymphocyte count and major lymphocyte sub-populations were significantly below control values. At six weeks the B cell and Null cell counts were s t i ll significantly diminished. The function of T cells assessed by radioisotope uptake by phytohaemagglutinin-stimulated lymphocytes and by delayed skin hypersensitivity reaction to dinitrochlorobenzene was impaired during the acute stage and this persisted for six weeks. No important abnormalities were detected in serum immunoglobulins and complement components. Partial reversal of immunological suppression caused by measles was therefore demonstrated at 6 weeks after the appearance of rash. Demonstration of a persistently defective delayed hypersensitivity in those who recovered made i t unlikely that this anergy was important in the development of chronicity. Complement abnormalities were similarly unrelated to progression to chronic lung damage. ( Children who recovered, when studied at six weeks, appeared to be worse o f f immunologically than those with established chronic chest disease following measles. Children with chronic chest disease were studied 6 - 1 6 weeks after onset of rash, by which time the partial reversal of immune deficiency, noted at 6 weeks, would be complete. Among the group of children studied during the acute rash of measles there were five who subsequently died and one who progressed to chronic chest disease. Results in these six children were compared with those in six age-matched children who recovered from measles within a week. In the children who subsequently died or developed chronic pneumonia, immunosuppression was more pronounced during the acute rash ( i . e ., 3 - 2 0 days before death) than in the children who recovered. The absolute total lymphocyte count (T and B cells) was s i g n i f i c a n t ly lower in those who died or developed chronicity. Mean serum C, was also lower in this group. There were no significant differences between the two groups for total white c e l l s , neutrophils, Null c e l l s, cells with both T and B cell markers, other complement factors, serum immunoglobulins and phytohaemagglutinin stimulation of lymphocytes. The total lymphocyte count in a further nineteen patients with measles who had died, studied retrospectively, was s i g n i f i c a n t l y lower than that in twenty-seven patients with measles who recovered. Children whose outcome was poor generally had absolute lymphocyte 3 counts below 2000 cells/mm whereas those who recovered had values above this level. (iv) Therefore children who w i l l die or develop chronic chest disease can be often distinguished, within two days of the appearance of the rash, from those who w i l l recover. In order to test the v a l i d i t y of this conclusion based on results obtained from a small sample the study was extended so as to increase the number of patients with measles who had severe lymphopenia (< 2000 cells/mm3). Seventy seven per cent of 30 children who had severe lymphopenia within 2 days of appearance of rash f a i l e d to recover: 30% died from pulmonary complications within a few days to two months of the onset of the exanthem while 47% developed chronic lung damage. This was s i g n i f i c a n t ly worse than the outcome in 30 children with lymphocyte counts above 2000 3 cells/mm , of whom 67% recovered, 33% developed chronic chest disease and none died. Persistence of severe lymphopenia (which was due to reduction 3 in both T and B cells) in those with i n i t i a l counts below 2000 cells/mm , for at least fifteen days after onset of rash, remained a good predictive index of morbidity and mortality. Reversal of immunoparesis in those with i n i t i a l severe lymphopenia was slower and less complete 42 days from the appearance of the rash in children who subsequently died or progressed to chronicity than in those who recovered. All patients who died f a i l ed to produce an adequate or sustained antibody response to measles. The results of these studies suggest that long term pulmonary and possibly neurological sequelae of measles are probably due to a transient widespread immunoparesis during early measles with persistent defects in specific immunity to measles and probably other viruses, whereas recovery is due to less severe effects of shorter duration. (v) In order to answer the question why some children do badly and others well after measles, studies on the HLA frequencies and measles antigen load have been undertaken in children with severe lymphopenia. Results of viral load are inconclusive and those of HLA suggest a trend towards histocompatibility linked genetic susceptibility to the development of severe lymphopenia in measles associated with HLA AW32. The therapeutic implication of these studies is that children with measles who are at risk for death and chronic disease can be identified early in the disease and intervention at this stage may reverse the severe immunosuppression which leads to rapid demise or modify the immunopathological changes progressing relentlessly in some cases to permanent lung and brain damage and occasionally to death.
Nephrotic syndrome in African and Indian children in South Africa.
(1981) Adhikari, Miriam.
There are comprehensive accounts of the nephrotic syndrome in childhood in temperate countries. Many of the important features of this disease have been known for close on to two decades. The causal link between malaria and nephrosis in tropical Africa has also been recognised and documented for a similar length of time. Very little was known of the nephrotic syndrome in the sub-tropical zones of Africa where malaria is not endemic. Anecdotal evidence in South Africa suggested that African children with this disease appeared to have steroid resistant nephrosis and a more protracted clinical course than expected from prevailing accounts in the literature and that Indian South African children generally responded to steroids. This thesis is the result of detailed investigations in to this disease in African and Indian children in Durban, South Africa. 2. Preliminary Study A preliminary study was undertaken in which 53 (12 African and 41 Indian) children with the nephrotic syndrome defined by clinical and biochemical criteria 1 ii were studied. Renal biopsies were not available on these patients. The results revealed that two thirds of the African children were over 5 years of age and 50% were males. Of the Indian children 50% were under 5 years of age and 50% were males. Nine African children were treated with steroids and 8 did not respond whereas 31 of the 39 Indian children treated clearly responded to steroid therapy. In addition 5 Indian patients were treated with cyclophosphamide and 3 responded. On follow-up 7 of the African children had persistent proteinuria, 2 experienced remissions and 3 were lost to follow-up. All the Indian patients experienced remissions. The differences between the 2 groups of nephrotic patients were quite striking and therefore a more detailed prospective study of this problem was undertaken. 3. Prospective Study of Primary Nephrotic Syndrome One hundred and seventy children of whom 104 were African and 66 Indian with primary nephrotic syndrome were studied. In both racial groups the male sex dominated, Indian children tended to present iii at a younger age group whereas African children presented at two peak ages, 5 years and between 5 - 10 years. 3.1 Histological Differences The histological types found on light microscopic examination of renal tissue were distinctly different between the African and the Indian children. The majority (85.6%) of the African children had 'obvious' glomerular lesions, the commonest being extramembranous nephropathy (29.8%). Although the proliferative group was the single largest group (40%) none of the subgroups exceeded the extramembranous type in their number. Minimal change accounted for only 14.4% of the African children with nephrotic syndrome. The majority of Indian children (72.7%) had minimal change on light microscopy, 9.1% focal glomerulosclerosis and 12.1% had proliferative changes. 3.2 Immunofluorescence Immunofluorescent studies also indicated differences between the two groups of patients. Generally, heavier deposits of immunoglobulins iv and complement components were identified on renal biopsy specimens of African children. This occurred even in MCNS where most African children had heavy IgG, light IgM, IgA and complement components whereas only a few of the Indian children had light IgM deposits. Similar differences were observed in diffuse mesangial proliferative glomerulonephritis and focal glomerulosclerosis where the numbers of patients were comparable. 3.3 Presenting Features Clinical features at presentation in the two groups were different, as expected from the nature of the histological findings in each group. In the African children (all histological groups) haematuria occurred in 35.5%, hypertension 16.3% and renal failure in 2.9%. The clinical features in the Indian children were not too different from MCNS elsewhere. Haematuria occurred in a small percentage (3%) of MCNS but was more frequent (10.7%) in other groups. Hypertension and renal failure occurred infrequently in histological categories other than MCNS where they did not occur at all. 3.4 Course and Outcome In view of the above it was not unexpected to find that the clinical course and outcome in the two groups were quite dissimilar. African patients in certain of the histological groups fared reasonably well, but none of the groups had the excellent prognosis of Indian MCNS. 3.4.1 Minimal Change One third of the African MCNS patients remitted and this was unrelated to steroids. The remainder who were followed for a reasonable duration of time remained proteinuric. None developed signs of serious renal impairment (azotaemia, hypertension). Indian MCNS experienced an excellent prognosis with 97.8% achieving remission and 81.6% being steroid sensitive. One third of these patients had a single episode of nephrosis while frequent relapses occurred in 28.2%. 3.4.2 Extramembranous Nephropathy Patients with extramembranous nephropathy, the largest group in the African patients, experienced hypertension more often (20%) vi and remission less often (30%) than do children in temperate climates. The clinical presentation, course and outcome in the majority of these patients were similar to adults with extramembranous nephropathy. 3.4.3 Proliferative Glomerulonephritis The patients in the proliferative group had a variable outcome depending on the subgroup to which they belonged. In diffuse mesangial proliferation, African patients had a higher incidence of hypertension and fewer remissions and fared less well than Indian patients. The diffuse endocapillary glomerulonephritis, membranoproliferative and focal proliferative nephritis groups of patients suffered severe disease with a failure to remit and progression to death. In the diffuse exudative group, remissions occurred or proteinuria persisted but severe relapse and death did not occur. The worst prognosis was in the focal proliferative group with the highest incidence of persistent relapse. 3.4.4 Focal Glomerular Sclerosis Focal glomerular sclerosis was an unusual vii histological diagnosis in the African child (3.9%) with a poorer prognosis (persistent proteinuria or death) when compared to Indian children in whom one third remitted and the rest had persistent proteinuria. 3.4.5 Tropical Nephropathies It is difficult to comment on the course of the tropical nephropathy (not related to malaria) and tropical extramembranous groups as the numbers are small. However, in tropical extramembranous, none remitted (all African children) and in tropical nephropathy one Indian child remitted but one of 2 African children died and the other had persistent proteinuria. 3.5 Response to Therapy Perhaps the most important practical aspect of the nephrotic syndrome in the African child was the response to steroid therapy. Thirty two African children were given steroid therapy. Thirty (93.7%) did not respond. Five children deteriorated or died during steroid therapy. Very few patients (4) were given cyclophosphamide and none responded. viii Generally intravenous albumen, diuretics and a high protein diet were not very effective in those patients with severe, clinical disease but were of benefit in milder disease. Indian children taken as a whole, responded well to steroid therapy. Seventy-eight percent of the whole group responded to steroids and 21.4% developed cushingoid features. Of the 19 Indian children (all MCNS) treated with cyclophosphamide 63.2% responded of whom about a quarter got toxic side effects (alopecia, darkened nails and leucopenia). Chlorambucil therapy in 4 children (all MCNS) was successful in all. 3.6 Complications Serious infections (septicaemia, peritonitis, urinary tract infection, meningitis, arthritis, osteitis, measles, chicken pox) occurred in 8.7% of the African patients. Eighteen percent had less severe infections. Just over a quarter of the Indian children suffered severe infections. The majority of these patients were MCNS and about 50% were on steroids or cyclophosphamide at the ix time of their infection. Renal biopsy complications were minor, these being abdominal pain and tenderness or transient haematuria. A few patients developed renal haematomas which were detected or monitored by ultrasonography. The single serious complication was the development of a renal abscess at the biopsy site requiring partial nephrectomy. 3.7 Mortality The overall mortality was 5.8%. Seven of the 10 deaths were African children in the Proliferative Group and 3 of the 10 deaths were Indian children. 4. Secondary Nephrotic Syndrome The secondary nephrotics formed an interesting group of patients. Of the 22 patients classified as secondary nephrotics 11 (50%) were related to streptococcal infection either as rapidly progressive glomerulonephritis or transient NS following APSGN. HBsAg was detected in the blood of 8.6% of the African patients. However the HB sAg carrier rate in this age group is 7.4%.The incidence in these patients probably reflects the high incidence in this population group. Collagen vascular disease occurred in 2 patients, both Indian. 5. Conclusions and Recommendations The results of this study demonstrates the strikingly different incidences of the various histological categories in the two race groups studied with a less favourable prognosis and fewer remission rates being achieved in African children. Indian children had more serious infections more often than African children. Steroid and immunosuppressive agents were of no value and probably hazardous in the African child. Some patients deteriorated on these drugs. Indian children who had an excellent response to these drugs were however at significant risk of developing serious infections. Why African children in Durban develop obvious glomerular lesions has not been established. Known or possible aetiological agents such as malaria, schistosomiasis, streptococcal infections and collagen diseases have been excluded. The answer to the above question may in fact lie in genetic predisposition,host factors and environmental influences, either singly or in combination, predisposing to the development of obvious x i glomerular lesions. These require more intensive investigation and judging from the yield of similar studies in other areas of the world expectations have to be guarded.
Aids for the early diagnosis of tuberculous meningitis (TBM)
(1985) Ramkissoon, Arthi.; Coovadia, Hoosen Mahomed.
Mortality and morbidity rates associated with tuberculous meningitis (TBM) are substantial. The average duration of the untreated disease from onset to death is about 17 days. The prognosis of TBM is known to correlate with the stage of the disease at the time of diagnosis and commencement of chemotherapy. Early diagnosis improves the chances of recovery without neurological sequelae. Early diagnosis is a problem because the presenting symptoms are non-specific and the onset of the disease is typically insidious. To date no single test is available that is totally reliable and specific for TBM. I have attempted to develop a reliable and easily applicable test for the diagnosis of TBM. In fulfilling this objective, the work undertaken may be divided into three major sections:- 1. Detection of soluble Mycobacterium tuberculosis antigens in the cerebrospinal fluid (CSF) of patients with TBM and in control groups by using Mycobacterium bovis BCG antigens. The technique used was that of inhibition enzyme-linked immunosorbent assay (ELISA). The principle of this technique is illustrated in Fig. 5. 2. Detection of soluble M. tuberculosis antigens in the CSF of tuberculous and control groups of patients by using antibodies raised against M.bovis BCG. The technique used was that of the double antibody sandwich ELISA. An outline of this ELISA is given in Fig. 6. 3. Correlation of chloride levels in the blood and CSF of patients with tuberculous and other forms of meningitis. It has been established that the SERUM/CSF ratio of bromide tends towards unity in patients with TBM because the permeability of the blood-brain barrier is impaired. Since both bromide and chloride are chemically similar (both being halides), it was thought that a similar pattern may exist for BLOOD/CSF chloride ratios; and this was investigated. The method used for the INHIBITION ELISA had to be standardized before the samples could be tested. This involved investigating the acceptability of various microtitre plates; determination of the optimal working dilutions for the coating solution and conjugate; and determination of optimal conditions for the various incubation periods, both in terms of time and temperature. A total of 70 specimens was tested. These consisted of 25 normal CSF controls; 25 pleural and ascitic fluid samples; 10 TBM samples, and 10 bacterial meningitis CSF samples. It was found that a distinction existed between the absorbance values obtained from positive TBM CSF samples (Mean 0,658 + 0,043) and that from normal CSF samples (Mean 1,089 + 0,224). The mean absorbance of the culture-positive bacterial CSF's also differed significantly from the other 2 groups (Tables VII; IX). Some overlap occurred amongst the absorbance values of bacterial culture positive CSF's (Range 0,975-0,879) and normal CSF's (Range 1,486-0,934). The mean absorbance value for bacterial positive CSF samples (0,920 _+ 0,029) differed significantly (p <0,01) from those of normal CSF (1,089 + 0,224) and TBM CSF's (0,658 + 0,043). The difference between the mean values obtained with tuberculous and non-tuberculous groups of pleural and ascitic fluid was also significant (p < 0,01). The method used for the DOUBLE ANTIBODY SANDWICH ELISA was that of Sada et al. (1983). Before the samples could be tested, the method had to be standardized and similar investigations to those for the INHIBITION ELISA were performed. In addition, antibodies raised against M.bovis BCG were conjugated to alkaline phosphatase since no commercial preparation was available. Unfortunately no distinction was recorded between negative and positive test specimens, even on repetition of the entire procedure. Measurement of chloride was done by a fully automated procedure using the BECKMAN ASTRA-8. A total of 149 samples were tested. Of these 10 were tuberculous, 34 were viral, and the remainder were bacterial meningitis. No pattern was established that could differentiate TBM from viral or bacterial meningitis. The results obtained are tabulated in Table III and illustrated in Figures 9, 10, and 11. In summarizing, the use of the INHIBITION ELISA technique for the accurate diagnosis of TBM seems promising. However, its validity in the clinical situation will have to be assessed further and with greater numbers of specimens before it can be adopted as a diagnostic procedure for TBM. OBJECTIVE. To determine 1. The ability and reliability of the INHIBITION ELISA1 technique to detect mycobacterial antigens in pleural, ascitic, and cerebrospinal fluids. 2. The accuracy and reproducibility of the double antibody sandwich ELISA in the detection of mycobacterial antigens in CSF of patients with tuberculous meningitis (TBM). 3. Whether a correlation exists between blood and CSF chloride levels in patients with tuberculous and other forms of meningitis.
The effect of corticosteroid therapy on growth in Black South African children with nephrotic syndrome.
(1986) Manikkam, Noel Edwin George.
The most useful drugs in the management of nephrotic syndrome are the corticosteroids. These drugs are as well known for their adverse effects as they are for their therapeutic advantages. The two most common paediatric side effects are suppression of linear growth and posterior subcapsular cataracts. Both of these untoward effects are insiduous and therefore less easily perceived. Although many workers have studied the growth inhibiting effects of the corticosteroids in the various diseases e.g. asthma, very little work was done to investigate these effects in patients with nephrotic syndrome. Furthermore, the Renal Clinic, King Edward VIII Hospital, Durban continues to use a daily regime of prednisone instead of the alternate day regime which is widely recommended to minimise growth retardation. This study was therefore undertaken to investigate the growth inhibiting effects of repeated courses of daily, high-dose prednisone in African and Indian children with nephrotic syndrome. All children with nephrotic syndrome with relevant data in their records and with no other chronic illness were selected from the Renal Clinic. Of the 125 selected, 87 children had been treated with prednisone for an average of 35,9 weeks and 38 had been treated symptomatically. The heights of those that received prednisone were measured at an averace of 77 weeks after completion of therapy. The mean height standard deviation score (SDS) of the treatment and control groups of Indian children were -1,06 and -0,92 respectively, both being between the 10th and 25th percentile, whilst the mean height SDS of the treatment and control groups of African children were -1,82 (just below the 5th percentile) and -1,77 (between the 5th and 10th percentile) respectively. From the results, it is evident that repeated courses of daily prednisone therapy, even when it exceeds 36 weeks, does not inhibit growth in both African and Indian children. Although there was no significant difference between the races and sexes with respect to growth and corticosteroid therapy, this study does confirm earlier reports that most of the African children with nephrotic syndrome had obvious glomerular lesions whilst most of the Indians had minimal change nephrotic syndrome.
The role of immunoregulatory cells in healthy and sick African children.
(1987) Kiepiela, Photini.; Coovadia, Hoosen Mahomed.
Abstract available in PDF.
Pertussis vaccination of African infants using acellular and whole-cell vaccines.
(1991) Ramkissoon, Arthi.
Conventional pertussis vaccine prepared from killed whole cell B. pertussis organisms has been in widespread use since the early 1950's. Despite marked reductions in the incidence of pertussis, the use of the vaccine has caused concern because of questions of significant adverse reactions. Whooping cough is not notifiable in South Africa, and there is consequently a paucity of hard data on efficacy; in addition few cases are proven. Incidence, prevalence, severity and transmission of the disease hence remain a matter of conjecture. In order to provide background information and determine baseline data for undertaking further studies, available clinical and epidemiological data on whooping cough (pertussis) in South Africa was collated. It was intended to compare the pattern of disease seen in this country with that known in other parts of the world. Clinical and epidemiological findings from 1525 whooping cough admissions (diagnosed on the basis of clinical criteria) obtained from 6 major infectious disease hospitals around the country for the period 1980-1987/1988 are reported. The data from Durban were available in some detail. Incidence, morbidity and mortality of the disease in South Africa, as elsewhere, was higher in infancy. Infants and young children were predominantly affected, with 31.3% of cases under 12 months of age and 7.2% less than 2 months. Mortality was disproportionately higher in infancy; 53 .2% of deaths were in those younger than 12 months of age. There was a slight female preponderance, both in respect of prevalence and mortality. Patients were admitted with pertussis throughout the year, although there was a peak during the winter months (May to October). The typical whoop accompanied the cough in 55.6% of patients . A raised white cell count was recorded in 66% of patients. The most commonly detected The average duration of hospital stay was between 1 0-13 days. Of those with vaccination records, 26% were unvaccinated, 44% had 1 or 2 doses, and 27% had been fully vaccinated with a whole-cell pertussis vaccine combined with diphtheria and tetanus toxoids. The picture, incomplete though it is, reveals a pattern of pertussis similar to that described in other developing countries. The study reveals huge gaps in our knowledge of this subject in South Africa. More research needs to be done, particularly with respect to improved diagnosis, prevention and treatment; further pertussis should be made a notifiable disease in South Africa. The whole-cell pertussis vaccine currently used in South Africa has not been adequately evaluated for post-vaccination events and immunogenicity. The development of new purified component pertussis vaccines, which appear to be safer than conventional whole-cell preparations and of equal or almost equal efficacy (although optimal vaccine composition remains to be defined), requires that the concept of early vaccination with this vaccine compared with conventional whole-cell vaccine be examined in order to optimise the immune response to these vaccines in infants; more especially since neonates do not appear to benefit from passive immunity. Acellular pertussis vaccine has not been evaluated previously in neonates. In order to address the problem of high morbidity and mortality from pertussis in early infancy; and the incorporation of the vaccine into routine vaccination schedules, a phase 11 trial of acellular and whole-cell vaccines was undertaken in very young infants. The effect of neonatal vaccination with acellular pertussis vaccine on subsequent immunity; and the immunogenicity and shortterm safety and reactogenicity of routine primary vaccination with acellular vaccine compared with conventional whole-cell preparations was investigated. Three hundred and forty-five healthy, full-term African babies were, enrolled in the study at birth; 58% of whom were successfully followed for 9 months. Infants were assigned to 1 of 3 vaccine groups in sequence at birth and received either acellular or whole-cell pertussis vaccine , combined with 0 and T (A-OTP or W-OTP) at 2, 4 and 6 months of age. Groups I and 11 received A-OTP and Group III W-OTP. In addition, at birth, Group I received an additional dose of A-OTP and Group 11, a saline placebo injection. No unvaccinated controls were studied for ethical reasons. Serologic IgG responses to 3 major protective antigens of B. pertussis, filamentous haemagglutinin (FHA), pertussis toxin (PT) and fimbrial agglutinogens 2,3 (AGG2,3), were measured by ELlSA in sera obtained at birth, and before vaccination at 2, 4 and 6 months and at 9 months of age. The incidence and nature of post-vaccination events were recorded for 14 days after each dose. A-OTP induced serum IgG responses to PT and FHA comparable with those reported in other studies, with peak PT titres occurring at 6 months of age after 2 doses in babies vaccinated according to the routine schedule (Group 11). Surprisingly, response to W-OTP was found merely to restore levels of antibody to PT and FHA to those found in cord blood after 3 doses of vaccine, which questions the immunogenicity of the South African product. Four doses of AOTP (Group I) did not produce a better antibody response than the 3-dose schedule. Incidence of all post-vaccination events to both acellular and whole-cell vaccines was low (85.96/1000 doses, 136.36/1000 doses and 76.30/1000 doses in Groups I, 11 and III respectively). Minor symptoms were more common in recipients of A-OTP, although no significant differences in rates were demonstrated. Neurologic post-vaccination events (without sequelae) occurred more frequently hi recipients of W-OTP. No infant vaccinated with A-OTP from 2 months of age (Group 11) experienced a neurologic symptom. The risks of major post-vaccination events cannot however be fully quantified In a study of this small size and diseases. A-DTP vaccination commencing at birth produced final antibody titres to PT and FHA which were superior to those of South African whole-cell vaccine but were considerably lower than when the vaccine was incorporated into routine schedules commencing at 2 months of age. The study findings suggest that acellular pertussis vaccines, whether given from birth or from the age of 2 months, appeared safer and produced a better serologic response than the South African whole-cell product which may have impaired immunogenicity. During the course of the above study, 11 full-term infants with pertussis infection (10 subclinical) were retrospectively diagnosed on the basis of ser~logic evidence. Of the infants with subclinical disease, all 10 had a ~ 4-fold rise in at least 2 different pertussis IgG antibodies and nine had ~ 4-fold rise in all 3 IgG antibodies measured. Seven infants had raised IgA antibodies to PT and FHA and 4 infants had raised IgA antibodies to AGG2,3. Subclinical infection provoked antibody production to multiple antigens to differing degrees. The role of various factors which may have contributed to asymptomatic infection were analysed, viz - household contacts; type of antibody response (clinical vs. subclinical; vaccinated vs. subclinical); maternally acquired antibody levels; vaccination status (number of vaccine doses received); age and gender; and nutritional status. SpeCial features of the study which require emphasis are: pertussis remained subclinical in unvaccinated babies (most of the subjects were unvaccinated). Subclinical infection followed incomplete primary vaccination with either acellular or whole-cell vaccines commencing at 2 months of age. Subjects were 8 months of age or younger and only 1 had completed primary vaccination. Other infections of infancy were commonly detected; 4 infants had upper Likelihood of subclinical infection was related to significantly lower levels of maternallyacquired pertussis IgG-AGG2,3 antibodies but not associated with infants' nutritional status. Subclinical pertussis is described in very young African babies at an age when the disease is most severe, and therefore has implications for infant morbidity and mortality; it is also relevant to disease surveillance and vaccine-efficacy studies . Some perinatal factors influencing vaccination were also explored . In this context we looked at: i. The acquisition of maternal antibodies to B. pertussis in paired mother-infant sera from both well -nourished and SGA full-term and pre-term infants, and infants who subsequently developed pertussis infection, and effect of these maternally-acquired antibodies on subsequent antibody responses to acellular pertussis vaccine administered soon after birth, and to acellular and whole-cell vaccines administered from the age of 2 months. if. The acquisition of maternal antibodies to diphtheria and tetanus (OT) in paired motherinfant sera from full-term and pre-term infants, and the effect of these maternallyacquired antibodies on serologic responses to neonatal OT vaccination followed by whole-cell OTP vaccination at 2, 4 and 6 months. Maternal antibodies were measured since little is known about materno-fetal transfer of pertussis antibodies, especially in African countries where inhibition of placental transfer might occur for a variety of reasons. Furthermore, the effect of peri-natal malnutrition and prematurity on transplacental transfer of diphtheria, tetanus and pertussis antibodies has not been conclusively established in these areas. sera with levels in the latter frequently being higher, Indicating active transplacental transfer of antibodies. The significant pertussis antibody levels in maternal sera were unlikely to be due to the currently used South African whole-cell vaccine (given the poor antibody response to PT and FHA shown in this study). It is assumed that the presence of these antibodies are the end result of natural infection and therefore that pertussis is widespread in the African community. Maternal and cord IgG-PT and AGG2,3 titres were significantly lower (p <0.05) and maternal IgG-FHA marginally lower (p ... O.05) in SGA infants compared to cohorts, although placental transfer was equally efficient in both groups~ This study has demonstrated that the high titres of maternally derived circulating B. pertussis antibodies do not have an inhibitory effect on the subsequent serologic response to acellular vaccine administered in early infancy (2 months) or with the first dose given soon after birth. Protective levels of diphtheria and tetanus antibodies were detected in 100% and 76% of cord sera in pre-term infants and in 85% and 67% of cord sera in full-term infants. Although the number of infants studied was too small to make a definite comment, there did not appear to be 'tolerance' due to neonatal diphtheria-tetanus vaccination of pre-term infants, or to high levels of maternally-acquired antibody. During analysis of the data from the phase 11 study of acellular pertussis vacclnes, 25 infants with protein-energy-malnutritlon (PEM) were detected on the basis of anthropometric indices. Seventeen infants were smaIJ-for-gestatlonal-age (SGA). of whom 9 developed PEM by the age of 9 months. Eight other infants developed post-natal PEM before the completion of the primary vaccination course. and extent of immunological impairment, if any, on the serologic responses to acellular vaccine and to conventional whole-cell OTP in SGA infants, and in infants who developed PEM before the completion of the primary vaccination course. The following indices were evaluated in malnourished infants; (i) anthropometric indices of nutritional status, (ii) intercurrent illnesses including pertussis infection, (iii) post-vaccination events, (iv) serologic responses to vaccination. Results were compared with those obtained in well-nourished (WN) age- and vaccine-matched cohorts. Overall, peak titres and seroconversion data of all 3 antibodies were not significantly different in malnourished infants though final anti-AGG2,3 titres (at 9 months of age) in Group III were significantly lower (p = 0.035). Although peak and final PT and FHA antibody titres in many SGA and malnourished infants were lower than in WN infants and peak responses were attained at a later age, malnutrition did not significantly affect the response to A-OTP. Peak and final AGG2,3 antibody titres were similar in SGA, malnourished and WN infants. Overall malnourished infants responded no less well to pertussis vaccination than did other vaccinees. Incidence of minor local and systemic post-vaccination symptoms was not significantly different in PEM and WN groups although induration at injection site and irritability were more frequently reported in the latter. No major neurologic post-vaccination symptoms to either vaccine were reported in SGA infants or infants with PEM at the time of vaccination. No significant differences was noted in the incidence of major symptoms in PEM as compared with WN infants. One male infant (Group I) who was malnourished at birth and who had been given 2 doses of AOTP, developed clinical signs of pertussis infection between 2 and 4 months of age. Pertussis antibody levels immediately prior to infection were not significantly different from those of un infected age-matched cohorts. The percentage of infants afflicted with common childhood illnesses were similar in PEM and WN groups (46 vs. 43.2%) although the former group incurred significantly more illnesses at an earlier age' (s6 months) (p=O.05, chi square). These findings, albeit preliminary given the small numbers of subjects studied, suggest that acellular pertussis vaccine may be incorporated into routine vaccination schedules followed in developing countries with the expectation that adequate antibody responses will be provoked in SGA infants and in infants who develop post-natal PEM and that the incidence of vaccinerelated adverse effects will be no higher than in WN infants. Further and more extensive studies are indicated before the use of acellular pertussis vaccines can be recommended for routine primary vaccination of infants in preference to whole-cell preparations in developing countries.
The role of parenteral phenobarbitone in the treatment of neonatal hyperbilirubinaemia.
(1993) Adam, Omar Farouk.; Adhikari, Miriam.
Abstract available in PDF.
Epidemiological and clinical studies of vitamin A in Black South African pre-school children.
(1993) Coutsoudis, Anna.
The ocular complications of vitamin A deficiency have been known for many years, however, recent studies have suggested that marginal vitamin A status enlarges the risk of common childhood infections and increases mortality. It is therefore important to assess the vitamin A status, and some of its consequences, in children who are most likely to be at risk for vitamin A deficiency as this has important implications for promoting the health of children and for formulating appropriate primary health care policies. In South Africa very little data is available on vitamin A nutrition of communities; therefore one of the objectives of this research programme was to document the vitamin A status of African children who, because of historical inequities, are most likely to be at risk for deficiency. Sound, epidemiologically based surveys of vitamin A intake and body levels were conducted in a typical established township (using dietary intake as the measuring tool) and in a typical peri-urban informal settlement (using serum retinol and conjunctival impression cytology as the measuring tools). These studies revealed that the majority (97%) of children living in the established township surveyed had an adequate intake of vitamin A, whereas 44% of the children in the informal settlement had low serum retinol levels (20 ug/dL), and 18% had insufficient vitamin A, as assessed by 2 abnormal disc specimens, using the conjunctival impression cytology test. In order to investigate the interrelationsnips between vitamin A, other micronutrients and some risk factors, an analysis was undertaken of anthropometry, parasite infestation and blood concentrations of vitamin E, calcium, magnesium, phosphorous, albumin, haemaglobin, serum iron and ferritin and percent transferrin saturation. Significant positive correlations were found between serum retinol and all the biochemical indicators of iron metabolism studied except for serum ferritin. Ninety one percent of the children sampled were infested with parasites. These results highlight the fact that in this population close interconnections exist among nutrients and suggest that attempts at correcting vitamin A deficiency in such communities should be based on comprehensive intervention programmes rather than on single nutrient replacement. The impact of infections on blood levels of vitamin A was investigated in African children with severe measles. In addition, substances related to vitamin A metabolism such as other micronutrients (zinc, vitamin E) and proteins (retinol binding protein, prealbumin, albumin) were measured in serum. In addition the changes induced in these substances by vitamin A supplementation (offered in a randomised, double blind, placebo controlled trial) were studied. Serum retinol as well as the other nutrients measured were significantly reduced early in the exanthem in measles patients as compared to healthy controls. Vitamin A and prealbumin levels on day 8 (of the intervention trial) were significantly increased in the supplemented group compared to the placebo group. vitamin A levels in serum correlated with those of retinol binding protein (RBP), prealbumin and zinc. These findings strengthen the hypothesis that hyporetinaemia during measles is the consequence of impaired mobilisation of retinol stores from the liver. The effect of reversing the temporary lowering of serum retinol concentrations during acute measles infections by supplementation with vitamin A was investigated in a hospital based, randomized, double-blind, placebo controlled trial. The two groups were comparable in known covariates of measles severity : weight/age centiles; overcrowding; rash; total 90% of the patients had blood lymphocytes; serum levels pre-albumin, RBP, vitamins A and E. of zinc, albumin, hyporetinaemia. Integrated Morbidity Scores ( IMS) derived from diarrhoea, herpes and respiratory tract infection (radiologically confirmed) were assigned on day 8, at 6 weeks and 6 months - these were reduced by 82%, 61% and 85% respectively in the supplemented group. This was mainly due to reduced respiratory tract infection. There was one death in the placebo group. At 6 weeks there was significant weight gain in the supplemented group. Despite the selected sample, attention to multiple covariates enhances the validity of the data obtained and supports the current WHO recommendations for vitamin A supplementation during measles. There are several mechanisms by which vitamin A is thought to have its effect of reducing morbidity, one of which is by improving immune responsiveness. This particular mechanism has not been adequately studied in children; most of the studies having been conducted in animals. The effect of vitamin A supplementation on selected factors of immunity in African children with complicated measles was therefore investigated during the randomized double-blind, placebo controlled, intervention trial described above. Placebo and treated groups had similar baseline characteristics. In the treated group there was a significant increase in total number of lymphocytes (day 42, P = .05) and measles IgG antibody concentrations (day 8, p = .02), both of which have consistently been shown to correlate more closely with outcome in measles than other immunological, clinical and radiological factors. Interleukin-2 (IL-2) and plasma complement (C3 ) values were unaffected by vitamin A supplement.at.Lon , These findings reinforce results from animal studies which show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation. In conclusion epidemiological and biochemical methods which were used to assess the vitamin A status of African children in South Africa revealed that overt vitamin A deficiency is not a Public health issue to the extent it is in the poor rice eating nations of the world. Marginal vitamin A deficiency is however prevalent in informal settlements. Interventions to reverse this marginal vitamin A deficiency should be incorporated in comprehensive programmes to ensure food security. Infections such as measles which increase utilisation and inhibit mobilisation from body stores are damaging to vitamin A homeostasis in the individual. The morbidity associated with measles can be reversed by high dose vitamin A supplementation during the acute phase of the infection. Improving immune responsiveness is one of the likely paths of vitamin A activity in decreasing morbidity from measles.
Studies on the mechanisms of proteinuria in kidney diseases of childhood.
(1994) Ramjee, Gita.; Adhikari, Miriam.; Coovadia, Hoosen Mahomed.
Abstract available in PDF.
Stress, resources and coping processes in chronic childhood illness.
(1994) Kunnie, Thilortheni Yogesveri Moodley; Loening, W. E. K.; Pillay, Anthony Lingum.
Abstract available in PDF.
Investigation into optimal amikacin dosing in children.
(1996) Forsyth, Nan Barbara.
Aminoglycoside antibacterial agents, such as amikacin, continue to play an important role in the treatment of Gram-negative infections. However, although extremely effective, they are not without potential adverse events, the most important of which being nephro- and ototoxicity. Research into factors thought to influence both the efficacy and toxicity, has challenged the rationale upon which these agents have classically been dosed. Various studies in adult patients have found that a new approach to dosing (use of single daily administration) has equal or greater efficacy or safety compared to the standard multiple daily dosing of these agents. Similar studies comparing regimens in children are few, and as yet no comparative investigation has been performed using amikacin in children (as a separate and distinct group). Additionally, in evaluating the impact of altering dose regimens, it is imperative that the documented age-related aminoglycoside pharmacokinetic alterations, be taken into account. Amikacin pharmacokinetic parameters (determined using traditional methods) have been previously published for various (usually small) groups of children. However, population parameters are not currently available for South African children . This study therefore aimed to investigate optimal amikacin dosing in children by studying: a) the comparative efficacy and toxicity of two dosing regimens, and b) the population pharmacokinetic parameters derived using one of the alternative approaches capable of utilising routine, sparse serum drug concentration time data. This investigation was conducted in the paediatric surgical and burns wards of King Edward VIII Hospital , Durban. Study patients (0.6-12 years) received amikacin either once daily (15mg/kg) or twice daily (7.5 mg/kg) by slow intravenous bolus. Concomitant medication was given as prescribed. Regimen efficacy (favourable, unfavourable or indeterminate outcome) was assessed by patient temperatures, clinical improvement and white cell counts. Clinical nephrotoxicity was evaluated by changes in serum creatinine, and renal tubular damage (investigated in a small subgroup of patients) was indicated by detection of urinary low molecular weight proteins. Ototoxicity (cochleotoxicity) was assessed by pure tone audiometry. Pertinent demographic and treatment details (amikacin concentration time data) were recorded for the population pharmacokinetic analysis. The Nonlinear Mixed Effects Model (NONMEM) programme was used to derive appropriate models describing clearance (CL) and volume of distribution (V), as well as mean values of these pharmacokinetic parameters for this population. Fifty four patients were entered into the regimen assessment. Patients in the single daily regimen (n=27) had significantly greater (p<0.05) mean (SO) peak (±0.5 hour post-dose) serum amikacin levels (37.7 (6.9) mg/L) as well as cumulative dose (91.5 (26.5) mg/kg) and duration of therapy (5.7 (1 .5) days) when compared with those of the twice daily group (19.5 (3.7) mg/L, 70.1 (26.1) mg/kg and 4.6 (1 .6) days respectively). No statistically significant differences were found between the groups in terms of outcome (18/24 and 22/25 patients in the once and twice daily dosing groups had favourable outcomes; there were no unfavourable outcomes). Pure tone audiometry (evaluated post-therapy , in 20 patients from each dosing regimen) revealed no statistically significant differences between the number of patients in the two groups with possible drug-related ototoxicity. None of the patients assessed (including an additional 14 patients with burn injury) developed clinical nephrotoxicity. Urinalysis was performed in 17 amikacin treated patients (9 and 8 from the once and twice daily dosing regimens respectively) and 9 control subjects. Low molecular weight proteinuria was absent in all of the latter patients except one, in whom pre-existing renal disease was suspected. Tubular dysfunction ascribed to possible drug effect was detected in similar numbers of patients in the two treatment groups (3 and 2 patients in the once and twice daily dosing groups respectively). In the pharmacokinetic assessment (156 serum levels from 82 patients) using a one compartment model, the final models which best described the data were as follows : CL (Uhr) = 0.271 x age(yrs) + 2.46 x body surface areatrrr'), V (L) = 7.34 x body surface areatrn") Other fixed effects tested, which did not render the data more probable, included serum creatinine measurements at the start of treatment, gender, presence of burn injury and drug regimen. Interpatient variation was 15% and 18% for CL and V respectively, with intrapatient variation or residual error of 10%. The weight adjusted population parameter estimates (95% Confidence Interval) for this group were CL =0.180 (0.175 ,0.185) Uhr/kg and V =0.293 (0.286, 0.300) Ukg, which are within the range of values published previously for other children of similar ages. The findings of this investigation , consistent with those of other similar studies, indicate that daily amikacin administration (in combination with a B-lactam), to children with normal renal function, has similar efficacy to, and no greater toxicity than multiple daily dosing. However, the role, if any, of the significantly greater cumulative dose and duration of therapy in the daily dosing group is unknown. As uncertainty remains regarding the precise duration of certain post-exposure events (and hence, the ideal duration of the interdose interval), and with the rapid drug clearance in this group of patients , future in vitro and in vivo investigations may shed even further light on the optimal dosing approach in these patients.
Human immunodeficiency virus-1 infection and the acquired immunodeficiency syndrome in African children : natural history from birth to early childhood.
(1999) Bobat, Raziya Ahmed.; Coovadia, Hoosen Mahomed.
Background: in 1987, the first child with HIV-1 infection was identified in the paediatric wards at King Edward VIII Hospital in Durban. This made paediatricians aware that the epidemic had spread to the children of KwaZulu/Natal. Although information on transmission and natural history was becoming available from developed countries, little was known about the disease in developing countries. It was important to determine transmission rates and disease patterns in the local population, in order to appropriately counsel women, and for management of infected infants. In addition, with resources for laboratory diagnoses being limited in developing countries, much emphasis had to be placed on clinical findings for identification of infected children. In 1989, a retrospective analysis was made of the HIV-infected children seen over a 2-year period, between 1987 and 1989. Nine such children were identified and their clinical and biochemical features were described. It was concluded that HIV infected children presented with an identifiable pattern of signs, fairly similar to that described for children in industrialised countries. With these findings, a prospective study was undertaken, to determine the vertical transmission rate, the factors affecting this rate, and natural history of vertically transmitted I-IIV-1 infection. ix KwaZulu/Natal, being at the epicentre of the epidemic in South Africa, was a natural site for the study. Patients and Methods: a trained research worker was placed in the antenatal clinic at King Edward VIII Hospital for the specific purpose of educating, counselling, and testing of all women attending the clinic. Women attending the clinic for the first time in the index pregnancy were offered HIV testing if informed consent was obtained. Blood for HIV serology was drawn at the same time as sampling for the obligatory syphilis serology. The acceptance rate for sampling was > 95%. The majority of the women attending the clinic were black, and first attendance was generally late, into the third trimester. The same research worker was responsible for post-test counselling which was offered to all the women, not only those who tested positive. This research worker was also responsible for obtaining maternal consent for entering the newborn infant into the study. All newborn infants were seen within 48 hours of birth. At this time they were examined, growth parameters were recorded, and initial blood samples taken. These infants were then followed-up at 1 month, 2 months, 3 months, then at 3-month intervals up to 18 months, then at 6-month intervals. At each visit, a thorough clinical examination was performed, growth measurements taken, and development assessed. Record was made of any interim illness and visits to health centres, and of hospital admissions. Method of feeding was note& and details on immunisation obtained from the child's immunisation card. The children received all the x routine childhood immunisations according to the national regimen, based on WHO recommendations. Mothers were asked to bring the child to the follow up clinic for any problem, so that episodes of illness would not be missed. The women were reimbursed for transport costs to encourage follow up visits. Calculation of transmission rate and classification of infection status were made according to the recommendations of the Ghent workshop. Children were regarded as infected if they were antibody positive at 18 months or had an HIV related death. They were classified as uninfectd if the antibody test was negative at 9 months of age. Those infants who were lost to follow up before the age of nine months whilst still antibody positive and those whose cause of death could not be determined, were classified as indeterminate. The diagnosis of AIDS was based on the WHO criteria. Blood samples were taken at birth, at age one and three months, then at three month intervals to 18 months; thereafter at six month intervals. Sera were tested for HIV1 antibodies by a commercial enzyme-linked immunosorbent assay,ELISA. Samples that tested positive were confirmed by two tests, a Roche Elisa and by an immunoflourescent assay (IFA). A sample was regarded as being positive if both the second ELISA as well as the IFA or the Western Blot tested positive. xi Results: between October 1990 and March 1993, 234 infants and their 229 mothers were entered into the study. Those who did not attend a single follow up after birth were excluded from the study. The final cohort comprised 181 infants, of whom 48 were classified as infected ( including 17 deaths); 93 not infected, and 40 as indeterminate ( including 8 deaths). Maternal Data: about 60% of the mothers were under 30 years of age and were multiparous; 18% tested positive for syphilis serology; 22.9% were anaemic during pregnancy, and 37% were delivered by caesarean section. Most women lived in urban areas, and 16% chose to bottle-feed exclusively. Vertical Transmission Rate and Factors affecting this Rate: the median vertical transmission rate was 34%, (95% confidence intervals, CI 26%-42%). This figure is similar to that found in most parts of Africa, but much higher than those for Europe and USA. The maternal factors found to be associated with an increased risk of transmission were vaginal deliveries and a low haemoglobin level during pregnancy. Breastfeeding, Transmission, and Outcome: breastfeeding was found to have an increased risk of transmission, by 15 % (CI 1.8-31.8). On assessing growth and morbidity, it was noted that breastfed infants were not protected against such common childhood infections as pneumonia and diarrhoea, and that failure to thrive occurred with equal frequency in both those breastfed as well as those receiving artificial feeds. Newborn Data: when comparing newborn data between those infants who were subsequently found to be infected with those who were uninfected, it was found that there were no major differences between these groups with regard to growth parameters and neonatal complications. However, those infants with rapidly progressive disease (those who died within 24 months), were noted to have lower mean birth weights and lengths, a higher frequency of low birth weights, and tended to have more neonatal problems. Clinical Manifestations: the first differences between the infected and the uninfected infants generally manifested from about 3 months of age. HIV infected children were identifiable by higher frequencies of thrush, lymphadenopathy, skin rash, and hepatosplenomegaly in the early stages, and later on with a higher tendency to neurological and developmental abnormalities, as well as of diarrhoea. Pneumonia was found with equal frequencies in both the infected and uninfected children. The HIV infected child could be distinguished fairly early in life by the combination of the manifestations described above. Progression to AIDS: AIDS was diagnosed in 44% of all the infected children during the study period. Ninety five percent of these children were identified by 12 months of life, showing a rapid progression of the disease Longitudinal Growth: when longitudinal growth parameters were analysed in this cohort, it was found that HIV infected children were stunted from as early as 3 months of age, and remained below the international standards into early childhood. Infected children were also found to be malnourished (i.e. weight for age below international means), from an early age, and this persisted throughout early childhood. Of note, the uninfected childrens' weights, although comparable to international means initially, dropped after the first year of life. However, both groups did not have significant wasting, when compared to international means. Mortality: there were 25 known deaths during the study period. Of these, 17 were classified as HIV-related, and 8 as indeterminate. The mean age at death was 10.1 months, with 83% of all the HIV-related deaths occurring within the first year of life. The commonest diagnoses at the ti me of death were diarrhoea, pneumonia, and failure to thrive; also, thrush was common, as were neurological abnormalities.
Optimum timing for vitamin A supplementation in children with diarrhoea.
(2001) Elson, Karin Inga.; Coutsoudis, Anna.
Vitamin A has well recognised benefits for the reduction in severity of diarrhoeal episodes but the impact of therapeutic doses given during diarrhoea on the biochemical and clinical outcomes is less clear. In this study these potential therapeutic benefits were investigated to establish the optimum time for vitamin A supplementation to improve vitamin A status. Establishing the optimum time for vitamin A supplementation during an infectious stage would improve cost effectiveness and clinical benefit. Young children (174) between the ages of 3 and 60 months with severe diarrhoea were randomised in a double - blinded placebo controlled trial into one of 2 groups. The 1 st group received 60 mg of retinol as retinyl palmitate on admission during the acute diarrhoeal stage. The 2nd group received the same dose of vitamin A once symptoms had resolved, usually between 3 - 7 days. At each of these two time points, children not receiving vitamin A were given an identical placebo dose. Baseline (day 0) and day 3 serum samples were collected for vitamin A, retinol binding protein (RBP) and other biochemical markers. At four and eight weeks after discharge both morbidity and weight gain were recorded. The modified dose response test (MRDR) was conducted at the eight - week follow - up to estimate vitamin A liver stores. Initially, most of the children presented with watery diarrhoea and dehydration and were clinically very ill. At day 3 plasma retinol concentrations improved in both groups viz. from 0.57umol/L to 0.97umol/L in the 1st group and from 0.49umol/L to 0.90umol/L in the 2nd group. Similar improvements were found in retinol binding protein viz. 21.28 mg/L to 31.06 mg/L in the 1st group and 17.05 mg/L to 24.80 mg/L in the 2nd group. At 8 weeks there was also no significant difference between the two groups either for serum retinol (0.69umol/L and 0.73umol/L respectively) nor for MRDR ratios (0.036 and 0.049 respectively). The MRDR results at 8 weeks indicated that these children did not have depleted vitamin A liver stores and that the low serum retinol levels seen at baseline were probably due to the acute phase response during an infectious episode. The results of these analyses showed no significant difference between the two treatment groups thus indicating that there was no benefit to giving vitamin A on recovery from an infectious episode instead of on admission, as is currently practised.
Hepatitis B virus-associated membranous nephropathy.
(2002) Bhimma, Rajendra.; Coovadia, Hoosen Mahomed.
Glomerulonephritis as an extra hepatic manifestation of chronic HBV infection has now been well documented [1,2,3,4,5]. HBV-associated nephropathy has been described in areas of both high and low endemicity [6]. In Africa HBV-associated nephropathy has been reported from the southern, central and northern regions [7,8,9,10,11]. In the southern African continent the prevalence of HBV-associated nephropathy appears to be higher than the rest of the continent [12]. In KwaZulu/Natal, South Africa, the prevalence of hepatitis B surface antigenaemia (HbsAg) in urban, rural and institutionalised children was reported to be 6.3%, 18.5% and 35.4% and the HBV exposure rates, as shown by the presence of any marker of HBV infection, 19.5%, 65.1% and 70.1% respectively amongst black children [13]. Prior experience of nephrotic syndrome (NS) and its association with HBV in black children, already published in a series of reports, showed HBV-associated nephropathy to be the commonest form of nephrotic syndrome among black patients in KwaZulu/Natal; membranous nephropathy (MN) being the commonest histological type reported [7,14]. The only other large series of HBV-associated nephropathy in southern Africa was from Cape Town of a large cohort of children, mainly of mixed ancestory (coloured), with a small number of black children [8]. There have been no other large studies of this condition amongst black children in Africa. We therefore undertook a series of studies to delineate the spectrum of this disease in black children with regard to the following: clinical presentation, laboratory findings, natural history, biosocial background, genetics (using HLA Class I and II antigens) as well as the impact of treatment and prevention by immunisation. We commenced these studies by reviewing our 20-year experience of 636 children with NS in Durban, South Africa for the period 1976- - 1995. Three hundred and six (48.2%) were blacks, 307 (48.2%) Indians and 23 (3.6%) were a mixed group (coloured); 91 (14.3%) could not be categorised and were excluded from the analysis. In black children, membranous nephropathy accounted for 43% of all cases of NS; 86.2% of these 306 children were associated with hepatitis B virus antigens [15]. This contrasts with the 2% - 5% prevalence of idiopathic membranous nephropathy reported in western countries [16]. We then proceeded to document the clinical features of this disease in black children. One hundred and thirty-three children with NS positive for HBV carriage were studied. In 70 patients the histological type was membranous; 46 of these 70 patients were followed up for a mean of 3.4 years (range 1-11). Spontaneous elimination of both HBsAg and HBeAg occurred in 10 (21.7%) of the 46 patients; 16 (34.8%) cleared HBeAg alone. Co-existing liver disease occurred in 18 (25.7%); hypocomplementaemia (low C3 and C4) in 22 (47.8%) and 5 (10.9%) of these 46 children respectively. Sixty-five (92.9%) of the 70 patients had normal renal function; 1(1.4%) impaired renal function; 3 (4.3%) chronic renal insufficiency and 1(1.4%) end stage renal disease at last hospital visit. Twelve (17.1%) of the 70 patients were in remission; all having cleared HBeAg. HBVMN was clinically indistinguishable from 24 children with idiopathic MN although biochemical characteristics were different. There were 23 patients with histological lesions other than MN. Forty patients with clinical, biochemical and serological findings similar to those with HBVMN and the other histological types, were unbiopsied. This report delineates the natural history of HBV infection in black South African children with NS, the majority of whom have MN. Disease remission in HBVMN parallels elimination of HBV antigens, particularly HBeAg. Comparison of HBVMN with idiopathic MN revealed clinically indistinguishable characteristics but unexplained biochemical differences [14]. Little is understood of the biosocial context in which HBV-associated nephropathy (particularly MN) develops. In the next two studies we evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated. In the first of these two studies, thirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of this study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridisation and nested polymerase chain reaction. Sequencing of the precore HBV region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein: creatinine ratio. Seventy-two (37%) of the 197 family members and household contacts were HBV carriers, and 53 (27%) had a protein: creatinine ratio greater than the physiological limit (protein: creatinine ratio <0.2). Abnormal proteinuria was defined by a protein: creatinine ratio 0.2. Continuous data was compared using analysis of variance. Categorical data were compared using Chi-square test or Fisher’s exact test where appropriate. A probability of <0.05 was considered significant. The frequency of abnormal proteinuria was not significantly different in those with [22 (30.5%) of 72] or without [33 (32%) of 104] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; p = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (p = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (p = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than in community-based controls. The 10 index HBVMN cases and 14 family members and household contacts that were tested all had HBV of genotype A. The results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria. This lack of association was a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak of HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors [17]. In the second study of the biosocial background in which the HBV carrier-state with MN develops, we used the same subjects. One hundred and twenty-three unrelated individuals from the communities of the index cases, negative for HBV, served as controls. In this study, proteinuria was assessed using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and protein: creatinine ratios. Patterns of proteinuria on SDS-PAGE were classified as glomerular, tubular or mixed; IgG and haptoglobulin were suggestive of MN. Seventy-two (36.9%) of the 195 family members and household contacts were HBV carriers; 21 (29.2%) of these carriers had evidence of proteinuria using SDS-PAGE. Twenty-eight (41.2%) of the sixty-eight members of the study group who were HBV negative and 26.8% of the controls also showed proteinuria on SDS-PAGE. This lack of association between HBV carriage and proteinuria remained when controlled for gender and family relationship. Also, HBV was not protective against the development of proteinuria. Age was associated directly with a glomerular pattern of proteinuria (p = 0.007). Those having a pattern of proteinuria suggestive of MN were more likely to have an abnormal protein: creatinine ratio (p = 0.001). Ten (59%) subjects with a membranous pattern of proteinuria and 19 (47.5%) with a non-membranous pattern of proteinuria had microscopic haematuria. Such a pattern of proteinuria was not significantly different between subjects and community based controls (8.7% vs. 6.5%, p = 0.5). Environmental exposures in these subjects may be responsible for the proteinuria, which probably reflects underlying glomerular basement membrane damage. Discordance between the HBV carrier-state and patterns of proteinuria in the study group suggest that interaction between specifically vulnerable individuals and HBV group suggest HBV and MN may not be causally related or that it reflects exceptional interaction between specifically vulnerable individuals and HBV [18]. From the above two studies we inferred that the pathogenetic mechanisms by which individuals with chronic HBV infection develop MN are probably dependent on interactions between viral, host and environmental factors; some evidence suggests a genetic predisposition. We therefore undertook another two studies to explore HLA associations in black children with HBVMN. In the first of these two studies, thirty black children, age range 2 to 16 years, with biospy-proven HBVMN, were the subjects of this study. HLA A, B and C antigens were determined using a two-stage lymphocytotoxic test. HLA DRB1* and DQB1* typing was done using sequence-specific primers. HLA class I and II antigen frequencies of the study subjects were compared to controls that were randomly chosen healthy blood donors from the same population. HLA DQB1*0603 was increased in patients with HBVMN compared to controls (chi-square 13.65, RR 4.3). DRB1*07 and DQB1*02 were increased in frequency in the study subjects but failed to reach statistical significance. There was no significant difference in the frequencies of class I antigens in the study group compared to controls. This study is the first report of HLA associations in black patients with HBVMN in whom Class I and II antigens were determined using molecular methodology. It shows a high frequency of DQB1*0603 in black children with HBVMN compared to controls suggesting a possible genetic predisposition to the development of HBVMN [19]. Following our findings of an HLA Class II association in black children with HBVMN, we proceeded to determine if HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria in the second study. We studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603 selected from the first study. Associations of HLA DQB1*0603 to HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven of the 70 (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative vs. those with DQB1*0603 who were HBV positive was not significant (anti-log sum = 2.0559 and average 0.23). When a similar calculation was done for abnormal proteinuria, there were no significant findings (anti-log sum = 3.8587 and average 0.43). This lack of association between HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 which distinguishes HBVMN from family members is the degree of proteinuria which is a reflection of the severity of glomerular basement membrane damage in the latter [20]. In the next study we proceed to investigate the efficacy of Interferon alpha 2b (INTRON A ®) in the treatment of HBV-associated nephropathy in black children. Twenty-four black children with biopsy-proven HBV-associated nephropathy were recruited into the study during the period April 1997 to June 1999. Five defaulted treatment and were excluded from the primary analysis. IFN 2b was administered for 16 weeks. Response to treatment was defined as loss of HBeAg, decrease in proteinuria, and prevention of deterioration in renal and liver function. A control group of 20 patients was followed up for the same period. Ten (52.6%) of the treated children responded with clearance of HBeAg by 40 weeks. None cleared HBsAg. All responders showed remission of proteinuria, 90% maintained normal renal function and 1 (10%) showed improvement of renal function. HBV DNA levels decreased in this group. Nine patients did not clear HBeAg; none showed remission of proteinuria, 2 showed deterioration of renal function. Liver enzymes rose during treatment but subsequently declined irrespective of response to therapy. No serious side effects were encountered. Only 5% of controls showed spontaneous clearance of HBeAg, and none had remission of proteinuria. Black children with HBV-associated nephropathy show accelerated clearance of HBeAg with remission of proteinuria following treatment with IFN 2b. IFN 2b was well-tolerated [21]. We then went on to investigate the impact of HBV vaccination in South Africa over 6 years on HBV-associated MN. HBV vaccine has resulted in a decline in the incidence of HBV carriage and hepatocellular carcinoma in South East Asia. Vaccine efficacy in Africa has not been adequately assessed. King Edward VIII Hospital, Durban, South Africa, is the only tertiary referral centre for the province of KwaZulu/Natal for children with renal diseases. HBV vaccine was introduced into the Extended Programme on Immunisation (EPI) in April 1995; vaccine coverage rates between 1995-2001 for children for the first, second and third doses were 85.4%, 78.2% and 62.0% respectively. HBV status was determined using radioimmunoassay (1984 – 1991) or ELISA. MN was confirmed on renal biopsy. The hospital average annual incidence of HBVMN was compared pre and post-vaccination, and according to age groups. Between 1984 and 2001 there were 119 children with HBVMN; the mean age was 7 years (range 1 to 14 years) and 101(85%) were males. The average annual rate ratio (aRR) per 105 child population was 0.25. The aRR of 0.03 for the years 2000-2001, was significantly lower than the aRR of 0.22 during the pre-immunisation period (1984 – 1994) [p = 0.003; RR = 0.12 (95% CI: 0.03 – 0.5)]. The aRR in 2000-2001 for children 0 – 4 years (0.00) and 5 – 10 years (0.09) were significantly lower than in the pre-vaccination years (0.16 and 0.46, p = 0.01 and 0.02 respectively). Thus, HBV vaccine, even at low coverage for the full EPI schedule, reduced the hospital incidence of HBVMN by six years [22]. From this series of studies we concluded that prior to the introduction of the HBV vaccine into the Expanded Programme on Immunisation in Children, HBV-associated nephropathy, particularly MN was the commonest form of NS in black children. Several studies have suggested on the basis of epidemiological, clinical and immunological evidence a causal association between chronic HBV carriage and the development of nephropathy. In our present series of studies we have findings that lend further support to the causal association between HBV carriage and development of nephropathy, particularly MN, in black children. We have shown that genetic and other environmental factors may also play a role in determining the degree of proteinuria. Those children with abnormal range proteinuria less than the nephrotic range show no association with HBV carriage or genetic factors with regard to HLA linkage. The efficacy of interferon treatment in elimination of the HBV and abrogation of proteinuria following clearance of the virus (particularly the HBeAg) as well as the impact of routine HBV immunisation in preventing HBV carriage and subsequent development of nephropathy lends further support to our findings. The impact of viral load has yet to be investigated.
Evaluation of an exclusive breastfeeding promotion programme in an informal settlement in Durban.
(2002) Bentley, Jane.; Coutsoudis, Anna.
Abstract available in PDF.
The antibody response to different measles vaccine strains given by the aerosol and subcutaneous routes to schoolchildren.
(2003) Dilraj, Athmanundh.; Coovadia, Hoosen Mahomed.; Cutts, Felicity T.
Abstract available in PDF.
The interaction between human leucocyte antigen-G and natural killer cells at the placental interface in HIV-1 infected pregnant women and the significance, if any, to in utero transmission.
(2007) Moodley, Shamala.; Carpenter, S.; Bobat, Raziya Ahmed.
This study was undertaken to investigate the relationship between Natural Killer cells and HLA-G at the placental barrier in HIV-I infected pregnant women and to establish the significance, if any, to in utero infection. Fifty-five HIV -I infected pregnant women were recruited into the study after consent was obtained. Blood samples were collected from both mothers and babies for viral loads and CD4+ cell counts. Placental samples were obtained from pregnancies at delivery and examined by immunoperoxidase immunohistochemistry methods using monoclonal antibodies to p24 antigens and Natural Killer (CD56+) cells. HLA-G expression was quantified using real-time polymerase chain reaction. Analysis of viral loads and CD4+ cell counts were undertaken in categories. No significant association was observed between the viral load of mothers and their CD4+ cell counts. Eighteen percent of the women in this study population had 5 log viral loads with a transmission rate of 0.27(95% Cl, 0.15 - O. 39). Maternal viraemia was significantly associated with transmission of infection to babies (p = 0.047). The odds ratio indicated that for every 1 log increase in maternal viral load the babies were 3.1 times more likely to acquire the infection (Exp (B) = 3.137 (95%CI, 1.015-9.696). Furthermore, the study found that a higher number of female babies were infected than males. Although not statistically significant the odds ratio indicated that female babies were 3.1 times more likely to become infected than males (Exp (B) = 3.110 (95%CI, 0.819-11.808). We report here the results of immunohistochemistry for p24 antigens and NK (CD56+) cells and compare them to the immunological responses of both mothers and babies at birth. HIV-1 antigens were detected in 94.5% of all placentas by immunohistochemistry. Infiltration of CD56+ was found in 98% of placental tissue. The analysis revealed that the presence of p24 antigens in placental tissue was not influenced by maternal viral load or CD4+ cell counts. Lower median NK cell values were observed in placentas of mothers with infected babies as compared with the uninfected cluster. Although not statistically significant, the risk of vertical transmission was increased 3.4 times more in placentas which had lower NK cell values. According to the odds ratio, babies CD4+ counts were affected by every 1 log increase in mother's viral load. Overall, maternal viral load emerged as a strong predictor for risk of infection from infected mothers to their infants. Our analysis indicated that female babies were 3.7 times more likely to acquire the infection than males. Using data obtained from real-time PCR we investigated the relationship between maternal viral load and the quantity of HLA-G expression (p = 0.045; 95%CI 1.029- 11.499). Logistic regression models revealed that mother's viral load was the strongest risk factor for vertical transmission. No statistically significant correlation was noted with HLA-G and viral transmission. However, the odds ratio indicated that the risk of infection increased by 1.3 with every 1 fold increase in HLA-G expression. An analysis of mother-to-child transmission rates by gender revealed that the odds ratio for transmission was 3.4 times more in female babies than in males. We then investigated the relationship between maternal viraemia and HLA-G expression. A positive correlation between maternal viral load and placental HLA-G was observed (p = 0.038). When gender susceptibility to HLA-G expression was explored a statistically significant association was observed in placental tissue of mothers with infected and uninfected male babies and HLA-G expression (p = 0.013). To conclude, the analysis found that HLA-G was up regulated 3.95 times more in placental tissue of mothers with infected babies than in mothers with uninfected babies.
HIV-1 specific T-Cell responses in chronic HIV infected children during continuous treatment and structured treatment interruptions (STI).
(2010) Reddy, Shabashini.; Ndung'u, Peter Thumbi.
BACKGROUND Sub-Saharan Africa has the highest number of HIV-infected individuals and limited treatment programs. The use of Highly Active Antiretroviral Therapy (HAART) has resulted in a considerable decrease in morbidity and mortality among HIV-infected individuals. Long-term use of HAART has several limitations relating to cost, drug toxicity and adherence. Structured Treatment Interruption (STI) has been proposed as a therapeutic approach which limits the exposure to continuous HAART, but retains the benefits thereof. The role of HIV-specific Tcell responses in the control of viraemia has not been well studied in children and it is not clear when these responses become detectable or whether they are associated with improved viral control. Furthermore, antiretroviral drug resistance is well documented in adults infected with HIV-1 clade B virus but comparable information is lacking for chronic paediatric clade C virus infection. This pilot study focused on a chronic HIV-infected paediatric cohort from Durban, South Africa, to assess the immunologic and virologic responses in perinatal HIVinfected children undergoing STI. METHODS Thirty chronic HIV-infected treatment naïve children were enrolled and randomised into either the treatment interruption or continuous treatment group. Longitudinal measurements of viral loads and CD4 percentages were done at scheduled intervals. Peripheral blood mononuclear cells (PBMCs) were screened for cytotoxic T-lymphocyte (CTL) gamma interferon (IFN-?) enzyme-linked immunospot (ELISpot) assay responses using 410 peptides which spanned the entire HIV-1 clade C proteome. Intracellular cytokine staining (ICS) was done to distinguish between IFN-? Gag-specific T-helper and cytotoxic T cell responses. Pre-HAART drug resistance mutations testing and HLA typing were done for all children. RESULTS There was a significant increase in the median CD4 percentage after HAART was introduced. Six children randomized to the STI arm did not undergo treatment interruption because their viral loads remained detectable at the time of scheduled interruption. Most HIV proteins were targeted in this paediatric cohort. Gag was the most frequently targeted HIV-1 protein (93.1%). In both treatment groups, there were broadening of T-cell responses, however, the magnitude of T-cell responses decreased over time on HAART. Drug-resistant mutations were detectable in 4/29 children before initiation of HAART. CONCLUSION In this pilot study, the HIV-1-specific CD8+ and CD4+ T-cell responses were detected before and during HAART. Although the treatment interruption period was short, there were no adverse outcomes in either the continuous or treatment interruption groups in terms of death or other clinical outcomes. This study suggests that it is important to continue to explore alternative treatment strategies in order to reduce cost and toxicity as well as to enhance adherence.

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