Perinatal transmission of HIV-1: lack of impact of maternal HIV infection on characteristics of livebirths and on neonatal mortality in Kigali, Rwanda.

We present the baseline results of a prospective cohort study on the perinatal transmission of HIV-1 in Kigali, Rwanda. HIV-1-antibody testing was offered to all women of urban origin delivering a live newborn at the maternity ward of the Centre Hospitalier de Kigali from November 1988 to June 1989; 218 newborns of 215 HIV-positive mothers were matched to 218 newborns of 216 HIV-negative mothers. The matching criteria were maternal age and parity. No differences in socioeconomic characteristics were observed between HIV-positive and HIV-negative women. HIV-positive mothers more frequently reported a history of at least one death of a previously born child (P less than 0.01) and a history of abortion (P less than 0.001). Most of the HIV-positive women were asymptomatic, but 72.4% of them had a CD4; CD8 ratio less than 1 versus 10.1% in the HIV-negative group (P less than 0.001). The frequency of signs and symptoms was not statistically different in the two groups, except for a history of herpes zoster or chronic cough, which was more frequent among HIV-positive women. The rates of prematurity, low birth weight, congenital malformations and neonatal mortality were comparable in the two groups. However, infants of HIV-positive mothers had a mean birth weight 130 g lower than the infants of HIV-negative mothers (P less than 0.01). The impact of maternal HIV-1 infection on the infant seems limited during the neonatal period.

Evaluation and simplification of the World Health Organization clinical case definition for paediatric AIDS.

The World Health Organization (WHO) clinical case definition for paediatric AIDS was tested during a 1-month period on 221 consecutive hospitalized children in Kigali, Rwanda. Relevant clinical features not included in the WHO case definition were also evaluated. Thirty-four out of the 221 children (15.4%) were HIV seropositive. Although the specificity of the WHO case definition was high (92%), the sensitivity and the positive predictive value (PPV) were low (41 and 48%, respectively). The following individual signs had a PPV at least equal to the complete WHO case definition: chronic diarrhoea (47%), respiratory distress secondary to lower respiratory tract infection (50%), oral candidiasis (53%), parotitis (67%), generalized lymphadenopathy (88%), and herpes zoster infection (100%). When logistic regression analysis was done on the nine variables included in the WHO case definition, confirmed maternal infection was the best predictive variable for HIV seropositivity in children (P less than 10(-5). We further excluded the serological status of the mother from the analysis and performed a stepwise logistic regression analysis on the 18 clinical signs and symptoms for which information had been collected. Those signs and symptoms contributing the most to the regression were: respiratory distress, chronic diarrhoea and generalized lymphadenopathy. Based on these findings, we propose a simplified clinical case definition for paediatric AIDS in Africa with better sensitivity, specificity and PPV than the WHO case definition. Further work is needed using this approach to develop case definitions useful for epidemiological surveillance and for case management.

PIP: The World Health Organization (WHO) clinical case definition for pediatric acquired immunodeficiency syndrome (AIDS) was evaluated over a 1-month period in 221 consecutive hospitalized children in Kigali, Rwanda. The median age of the children studied was 18 months (range, 1 month-14 years); 55% were boys. 34 (15%) of these 221 children were seropositive for the human immunodeficiency virus (HIV). Although the specificity of the WHO case definition was high (92%), its sensitivity was only 41% and the positive predictive value was 48%. The following individual signs had a positive predictive value at least equal to the complete WHO case definition: chronic diarrhea (47%), respiratory distress secondary to lower respiratory tract infection (50%), oral candidiasis (53%), parotitis (67%), generalized lymphadenopathy (88%), and herpes zoster infection (100%). Logistic regression analysis on the 9 variables included in the WHO case definition indicated that confirmed maternal HIV infection was the best predictive variable for HIV seropositivity in children. When maternal serological status (rarely available in Rwanda) was excluded from the analysis and a stepwise logistic regression analysis was performed on the 18 clinical signs and symptoms for which data had been collected, respiratory distress, chronic diarrhea, and generalized lymphadenopathy emerged as the signs contributing the most. On the basis of these findings, a simplified clinical case definition of pediatric AIDS is proposed for settings where resources are limited and HIV seroprevalence is high. According to this definition, pediatric AIDS should be suspected in a child presenting with 1 or both of the following clinical signs: respiratory distress secondary to lower respiratory tract infection and/or generalized lymphadenopathy. However, it is necessary to test this definition on a larger scale in Central Africa and in other parts of the world with different rates of HIV seroprevalence.

An assessment of the timing of mother-to-child transmission of human immunodeficiency virus type 1 by means of polymerase chain reaction.

To approximate the contributions of in utero, intrapartum, and postnatal transmission of human immunodeficiency virus type-1 (HIV-1) and to evaluate polymerase chain reaction (PCR) as a diagnostic tool for pediatric HIV infection, blood was collected at birth (cord blood), and at 3, 6-12, and 13-24 months in 218 children born to HIV-1-seropositive mothers in Kigali, Rwanda. Proviral DNA was detected by a double PCR using two sets of three primers (gag, pol, and env). Pediatric HIV-1 infection was defined according to serological and clinical criteria. The probability of having a positive PCR at a given time was calculated by a nonparametric method. Among children with unequivocal evidence of infection (n = 47), it was 30.5% on cord blood and 80.6% at 3 months. Thus, in children born to HIV-1-infected mothers, the estimated rate of transmission in the late postnatal period is 4.9%, and the rate of transmission in the intrapartum plus postnatal periods is 17.6%. Among 117 HIV-1-uninfected children born to HIV-1-infected mothers, six (5%) had a false-positive PCR on cord blood. These results should be taken into account in designing intervention trials aimed at reducing mother-to-child transmission of HIV-1.

Neurodevelopmental testing of children born to human immunodeficiency virus type 1 seropositive and seronegative mothers: a prospective cohort study in Kigali, Rwanda.

OBJECTIVE: The results of developmental testing of 218 children born to human immunodeficiency virus (HIV)-seropositive mothers and infected or uninfected themselves were compared with those of 218 children born to HIV-seronegative mothers in an ongoing cohort study in Kigali, Rwanda. METHODS: When the children were 6, 12, 18, and 24 months of age, a specific neurodevelopmental examination was performed blindly by study physicians assessing gross motor development, fine motor development, language acquisition, and social contacts. RESULTS: Only one acute severe HIV-related encephalopathy was identified among the 50 infected children. The proportion of abnormal neurologic examinations in HIV-infected children varied from 15% to 40% according to age and was always higher than in HIV-uninfected children born to HIV-seropositive and seronegative mothers (< or = 5% or less of abnormal examinations at each time period). After excluding those children with clinical acquired immunodeficiency syndrome (AIDS) from the analysis, the proportion of abnormal examinations in infected children was 12.5% at 6 months, 16% at 12 months, 20% at 18 months, and 9% at 24 months of age and was still more frequent than in HIV-uninfected children. The developmental delay was principally due to significantly lower gross motor scores. CONCLUSIONS: HIV-1-infected children are more frequently developmentally delayed than uninfected children during the first 2 years of life in this African population. This developmental delay is related to the AIDS stage of pediatric HIV infection.

Biological markers associated with prolonged survival in African children maternally infected by the human immunodeficiency virus type 1.

Sixteen children over the age of 5 years (Group 1) have been identified out of 537 children infected by human immunodeficiency virus and born to HIV-infected mothers, in Kigali, Rwanda. They were followed up for 2 years and compared with 16 younger AIDS patients (Group 2) and with 16 age- and gender-matched HIV-1 seronegative children (Group 3). Fourteen Group 1 subjects had anti-HIV-1 IgM which persisted during the entire study period, in 11 cases directed to HIV-1 envelope proteins. In vitro, immortalization of B lymphocytes by the Epstein-Barr virus confirmed a high production of IgM to envelope proteins. All these patients had anti-p 17 IgG which was not observed in 7 patients from Group 2. All 16 children mounted significant titers of neutralizing antibodies to HTLV-IIIB, and, in 8 patients tested, against two other HIV-1 strains, RII and MN. HIV-1-specific major histocompatibility complex (MHC)-restricted cytotoxic T cells were demonstrated in 3 of 5 of the subgroup who were tested. Prolonged survival over 5 years in children with maternally acquired HIV-1 infection is associated with a high titer of neutralizing antibodies, a persistent production of IGM to HIV-1 envelope proteins and of IgG to p 17.

Growth of human immunodeficiency type 1-infected and uninfected children: a prospective cohort study in Kigali, Rwanda, 1988 to 1993.

OBJECTIVE: To compare the anthropometric characteristics of children with and without HIV-1 infection. METHODS: In a prospective cohort study of 218 children born to HIV-1 seropositive mothers and 218 children born to HIV-1 seronegative mothers in Kigali, Rwanda, 3 groups were compared: infected children (n = 46); uninfected children born to seropositive mothers (n = 140); and uninfected children born to seronegative mothers (n = 207). Weight, height and head circumference were measured at birth, every 3 months during the first year of life and every 6 months thereafter. The weight-for-age, height-for-age, weight-for-height and head circumference-for-age mean z scores were calculated. RESULTS: The weight-for-age, height-for-age and head circumference-for-age mean z scores were lower among HIV-infected children than among uninfected ones at each time period. The reduction in the weight-for-age mean z score was the greatest between 12 and 36 months. The reduction in the height-for-age mean z score of HIV-infected children was persistently below 2 SD after 9 months of age. On the other hand the weight-for-height mean z score was not consistently lower in HIV-infected children when compared with uninfected ones. The anthropometric characteristics of uninfected children born to seropositive mothers were similar to those of children born to seronegative mothers. CONCLUSIONS: In this study HIV-infected children were more frequently stunted (low height-for-age) than uninfected ones. Wasting (low weight-for-height) was not common among HIV-infected children.

Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae from Rwanda, 1984-1990.

A total of 383 clinical isolates of Streptococcus pneumoniae, obtained from an equal number of patients in Kigali, Rwanda, was tested for resistance to penicillin G with a 1 microgram oxacillin disc. Of these isolates, 99 (25.8%) showed reduced zones of inhibition. By means of an agar dilution method, 21% all isolates were confirmed as relatively resistant (MIC > or = 0.12- < or = 1.0 mg/l) strains of Streptococcus pneumoniae (RRSP). A high degree of resistance to penicillin G (MIC > or = 2 mg/l) was not observed. Resistance to chloramphenicol (MIC > or = 8 mg/l) was found in 31% RRSP and in 6% penicillin susceptible strains (PSSP). Doxycycline resistance was common in both RRSP and PSSP strains. All isolates remained fully susceptible to erythromycin. Children more often harboured a strain giving a reduced inhibition zone than did adults (74/230 versus 25/153; P = 0.0005). A total of 32 serotypes or serogroups were identified, seven of them relating to 64.8% all isolates typed. Of all the isolates 84% belonged to a serotype represented in the 23-valent vaccine or to a cross-reacting serotype. Serotype 25, not included in the vaccine, accounted for 10.7% typed isolates from adults but only for 2.0% typed isolates from children. Results of susceptibility testing and clinical experience suggest that penicillin G, ampicillin and chloramphenicol should not be used alone as empirical treatment for pneumococcal meningitis in patients in Rwanda.

[Septic meningitis in children in Rwanda from 1983 to 1990. Retrospective study at the Kigali Hospital Center]. / Les méningites septiques de l'enfant au Rwanda de 1983 à 1990. Etude rétrospective au Centre Hospitalier de Kigali.

To assess septic meningitis in pediatric units in terms of the bacteriologic distribution, mortality, and groups at risk, we conducted a retrospective study in the pediatric department of the Kigali Hospital Center (Rwanda). Based on bacteriologic study of 1215 cerebrospinal fluid samples, there were 321 cases of septic meningitis due to identifiable germs and 68 involving cloudy fluid with no detectable germs, i.e. 1.5% of admissions to the Pediatric Unit of the Kigali Hospital Center. The most common organisms were pneumococcus (36.5%), Haemophilus influenzae (31%), salmonella (13%), and meningococcus (11.5%). Most of the children (75%) presenting septic meningitis were under the age of 5 years. Overall mortality was 38% with rates of 52% and 39% for cases involving pneumococcus and salmonella respectively. The predominant clinical symptoms of pneumococcus meningitis were coma (p:0.000055) and respiratory compromise (p:0.02). In contrast Haemophilus influenzae meningitis was associated with a lower incidence of coma (p:0.05) and malnutrition (p:0.017). Salmonella meningitis was characterized by a higher incidence of fever over 38.9 degrees C (p:0.025) and malnutrition (p:0.01). In patients with meningococcus meningitis, the incidence of convulsions appeared to be higher, at the threshold of statistical significance (p:0.052), whereas coma (p:0062) and respiratory distress (p:0.0024) were uncommon. Independently of etiology, no clinical symptom was associated with a statistically higher risk for death.

[Routine vaccinations in children and adults infected with HIV]. / Vaccination de routine et infection par le VIH de l'enfant et de l'adulte.

Five questions were raised in 1986 regarding routine immunization of children infected by the HIV: do vaccines protect these children, both in terms of immunogenicity and clinical efficacy? is immunization, particularly with live attenuated vaccines associated with an increased risk of adverse events? could the stimulation by vaccine antigens precipitate the course of paediatric HIV infection and therefore be dangerous? what are the clinical and epidemiological features of vaccine preventable diseases among HIV-infected children? what is the risk of nosocomial transmission of HIV associated with immunization practices? Based on the best available information, the WHO formulated recommendations in 1987 and updated them in 1989. These recommendations are in general agreement with those proposed during the same period in the USA and in France (table 1). This paper provides an update on the scientific knowledge in this field, focusing on routine childhood immunization in the context of HIV infection, especially in developing countries. The cases of bacillus Calmette-Guérin (BCG), measles vaccine, diphtheria-tetanus-pertussis and poliomyelitis vaccines are reviewed. For each of these antigens, the experience of the authors in Kigali, the capital city of Rwanda, is used as an example. A brief overview of the issue of adult immunization in the context of HIV infection concludes this review. Paediatric HIV infection should not be considered as a limiting factor in the implementation and the progression of the EPI worldwide. Experience accumulated over the last seven years, particularly in Africa, indicates that the WHO recommendations should not be modified.

Multiresistant Salmonella typhimurium systemic infection in Rwanda. Clinical features and treatment with cefotaxime.

Children with multiresistant Salmonella typhimurium (MRST) systemic infections, in total 246, were diagnosed during the study period. Of these, 220 had MRST without metastatic focal infections and 26 had metastatic focal infections (including 12 patients with meningitis). The median age of the children was 10 months. Diarrhoeal disease, measles and severe malnutrition were the most frequent causes of admission. Fever was found in 99% and diarrhoea in 72% of the patients, with respiratory symptoms in 72%. In 199 (81%) of the patients, the MRST infection was considered to be hospital-acquired. Of the 246 children, 159 were treated with cefotaxime. In this group, 16 of 152 patients died (10.5%). However, of the 87 children who did not receive cefotaxime, 64 died (74%). Relapses occurred in 4% of the patients with bacteraemia treated with cefotaxime. Our study confirms the high efficiency of cefotaxime in treating severe systemic infections with MRST.

Bacteraemia as predictor of HIV infection in African children.

In Rwanda, both HIV infection and bacteraemia represent major health problems among paediatric populations. We carried out of prospective study of determine if bacteraemia is a marker of HIV infection among ambulatory and hospitalized Rwandese children. All children presenting at the Department of Paediatrics of the Center Hospitalier de Kigali who had their blood cultured during a two-month period were eligible for the study. One hundred and thirty-five children were included in the study. A pathogen was isolated from 36 children (26.7%): S. typhimurium (10 cases), S. enteritidis (6), S. typhi (4), Str. pneumoniae (9). H. influenzae (6) and S. aureus (1). No association was found between bacteraemia and HIV seropositivity when all the children were considered. However, among patients less than 2 years old, bacteraemic subjects were more frequently (p less than 0.05) HIV seropositive (44%) than those with negative blood cultures (19%). Our study shows that in young children in Central Africa, the presence of bacteraemia may be an important marker of HIV seropositivity.

Broadly neutralizing, MN-like PND-directed antibodies in Rwandan children with long-term HIV1 infection.

Sera from 11 perinatally HIV1-infected Rwandan children with prolonged survival were tested in vitro for the presence of neutralizing antibodies against different HIV1 strains. These 11 sera from long survivor (LS) children were compared with 16 sera from Rwandan children with AIDS. Sera from HIV1-infected children exhibited the greatest neutralizing activity against HIV1MN cell-free infection. They also inhibited HIV1RII and HIV1LAI cell-free infection with lower titres. Higher neutralization titres were observed in sera from LS compared to the AIDS group, with a significant difference for HIV1MN and HIV1LAI strains. Sera from LS children also inhibited syncytium formation induced by HIV1MN-infected cells with higher titres than AIDS children. Sera from the HIV1-infected children showed reactivity to the HIV1MN V3 peptide, as well as to both the US/European and the African consensus V3 peptides. Higher reactivity was observed in sera from LS than from AIDS children, and the difference was significant toward the African consensus peptide. The LS children also had significantly higher V3MN IgG avidity than the AIDS children. These data support the notion that the humoral response to the V3 domain, associated with a broadly neutralizing activity, may be an important factor in the prolonged survival of these children. The specificity against HIV1MN also suggests that an antigenically MN-related strain may be prevalent in Rwanda, and that an MN-related principal neutralizing domain sequence could be an important determinant for candidate vaccines in this part of Africa.

Severe multiresistant Salmonella typhimurium systemic infections in Central Africa--clinical features and treatment in a paediatric department.

During a 21-month period, we observed an outbreak of severe systemic infections due to multiresistant Salmonella typhimurium among 66 children in the in-patient Department of Paediatrics of Kigali, Rwanda. These infections were more likely to occur in subjects who had stayed for a long time in the hospital for severe illness and/or malnutrition. The children usually presented first with mild to moderate diarrhoea and fever. Later, sever pulmonary involvement was often noted (rales: 58%; respiratory distress: 42%). Moreover, there were four cases of abscess, three arthritis and one meningitis. Of the 66 children, 48 were treated with cefotaxime. The fatality-rate among this group was 10.4%. The fatality-rate among the 18 other untreated patients was 77.9%, suggesting a high efficiency of cefotaxime against these strains of multiresistant Salm. typhimurium.

Infective and anti-infective properties of breastmilk from HIV-1-infected women.

Human immunodeficiency virus type 1 (HIV-1) is transmitted mainly by cell-to-cell contact. We postulated that transmission of HIV-1 through breastmilk could be favoured by the presence of infected cells, by deficiency of anti-infective substances in breastmilk, or both factors. 215 HIV-1-infected women were enrolled at delivery in Kigali, Rwanda; milk samples were collected 15 days, 6 months, and 18 months post partum. HIV-1 IgG, secretory IgA, and IgM were assayed by western blot, for the latter two after removal of IgG with protein G. In the 15-day and 6-month samples, we sought viral genome in milk cells by a double polymerase chain reaction with three sets of primers (gag, pol, and env). HIV-1 infection in the offspring was defined according to serological and clinical criteria. At 15 days, 6 months, and 18 months post partum, HIV-1 specific IgG was detected in 95%, 98%, and 97% of breastmilk samples, IgA in 23%, 28%, and 41%, and IgM in 66%, 78%, and 41%. In children who survived longer than 18 months, the probability of infection was associated with lack of persistence of IgM and IgA in their mothers' milk (adjusted chi 2 for trend, p = 0.01 for IgM and p = 0.05 for IgA). The presence of HIV-1-infected cells in the milk 15 days post partum was strongly predictive of HIV-1 infection in the child, by both univariate (p < 0.05) and multivariate analysis (p = 0.01). The combination of HIV-1-infected cells in breastmilk and a defective IgM response was the strongest predictor of infection. HIV-1 infection in breastfed children born to infected mothers is associated with the presence of integrated viral DNA in the mothers' milk cells. IgM and IgA anti-HIV-1 in breastmilk may protect against postnatal transmission of the virus.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) and its determinants: a cohort study in Kigali, Rwanda.

The authors report the results of the first 2 years of follow-up of a prospective cohort study on the mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) and its determinants which started in November 1988 in Kigali, Rwanda. The study sample consists of 218 newborns of 215 HIV-1 seropositive women matched to 218 newborns of 216 HIV-1 seronegative women of the same age and parity. They were followed every 2 weeks during the first 2 years of follow-up. HIV-1 antibodies were detected by enzyme-linked immunoadsorbent assay and Western blot at 3-month intervals. Two methods of calculating the mother-to-child transmission rate were used: method 1 combines the information provided by the persistence of HIV-1 antibodies at 15 months of age in children born to HIV seropositive mothers and the excess mortality in this group compared with the cohort of children born to HIV seronegative mothers; method 2 is a case-by-case evaluation of all the children born to HIV seropositive mothers. A logistic regression model was used to study the determinants of transmission. The probability of survival at 24 months of age was 81% (95% confidence interval (CI) 75-86) in children born to seropositive mothers, compared with 95% (95% CI 92-98) in children born to seronegative mothers (p < 0.001). The mother-to-child transmission rate calculated with method 1 was 25.7% (95% CI 18.8-32.5). With method 2, the medium estimate was 24.7%. In the multivariate analysis, a CD4/CD8 ratio < 0.5 was the only maternal factor statistically associated with an increased risk of mother-to-child transmission of HIV-1 (odds ratio = 2.9, 95% CI 1.2-7.2). The authors' findings present evidence for a higher mother-to-child transmission rate of HIV-1 in children born in Rwanda than in industrialized countries.

Metastatic focal infections due to multiresistant Salmonella typhimurium in children: a 34 month experience in Rwanda.

Nineteen out of 139 children with severe systemic disease due to multiresistant Salmonella typhimurium observed during a 34-month period in an in-patient department in Rwanda had focal metastatic infections. More than 80% of the invasive Salmonella infections were acquired in the hospital. Focal metastatic infections occurred after longer hospital stays than bacteremia (29.1 +/- 17.4 days as against 13.5 +/- 9.0 days, p less than 0.01) and were diagnosed more time after the first sign of infection (3.28 +/- 1.41 days as against 1.86 +/- 1.10 days, p less than 0.01). Bacteremia was documented in 13 of the 17 children with focal infection from whom blood cultures were obtained. Seven of 12 had positive stool cultures. The sites of metastatic focal infection were meninges (7 cases), soft tissue (5 cases), joint or bone (4 cases), pleura (2 cases), eye (1 case). The clinical course of meningitis was fulminant and 6/7 patients died before receiving adequate antimicrobial therapy. One child with meningitis and 9 patients with focal infections at other sites were treated with cefotaxime and were cured or improved.