Experience with the use of palivizumab together with infection control measures to prevent respiratory syncytial virus outbreaks in neonatal intensive care units.

Respiratory syncytial virus (RSV) frequently causes nosocomial outbreaks in general paediatric wards and occasionally in neonatal intensive care units (NICUs). Conventional infection control measures often fail to prevent the spread of RSV, and it can cause significant morbidity especially in preterm and young infants. We report our experience in preventing an outbreak on a NICU after RSV had been detected in a premature infant. The index case was a 34-day-old premature infant who presented with clinical infection and RSV was detected in a clinical specimen. There were 11 patients in the ward at the time including the index case. The RSV-positive patient was isolated, the ward closed to admissions and infection control measures were implemented. Two patients were transferred to another hospital. Palivizumab 15 mg/kg i.m. was given to all patients and no further cases occurred. All subsequent RSV tests on nasal secretions were negative. Palivizumab combined with conventional infection control measures appeared to prevent the spread of RSV in this NICU. Strategies for the prevention of RSV outbreaks on NICUs all recommend the reinforcement of routine infection control measures. Recommendations concerning the use of palivizumab range from monthly prophylaxis to all infants at risk, to prophylaxis of selected cases only. Currently there are no guidelines for the use of palivizumab in NICUs or for the control of RSV outbreaks.

Effect of antipyretic drugs in children with malaria.

A comparison of different antipyretics in children with malaria showed a small effect of naproxen, but not of metamizol, on the reduction of fever peaks. Antipyretic treatment had no effect on fever clearance and therefore should be used cautiously in the treatment of malaria.

Low interleukin-12 activity in severe Plasmodium falciparum malaria.

We compared interleukin-12 (IL-12) and other cytokine activities during and after an acute clinical episode in a matched-pair case-control study of young African children who presented with either mild or severe Plasmodium falciparum malaria. The acute-phase, pretreatment plasma IL-12 and alpha interferon (IFN-alpha) levels, as well as the acute-phase mitogen-stimulated whole-blood production capacity of IL-12, were significantly lower in children with severe rather than mild malaria. IL-12 levels, in addition, showed strong inverse correlations both with parasitemia and with the numbers of circulating malaria pigment-containing neutrophils. Acute-phase plasma tumor necrosis factor (TNF) and IL-10 levels were significantly higher in those with severe malaria, and the concentrations of both of these cytokines were positively correlated both with parasitemia and with the numbers of pigment-containing phagocytes in the blood. Children with severe anemia had the highest levels of TNF in plasma. In all the children, the levels in plasma and production capacities of all cytokines normalized when they were healthy and parasite free. The results indicate that severe but not mild P. falciparum malaria in young, nonimmune African children is characterized by down-regulated IL-12 activity, contrasting markedly with the up-regulation of both TNF and IL-10 in the same children. A combination of disturbed phagocyte functions resulting from hemozoin consumption, along with reduced IFN-gamma responses, may contribute to these differential effects.

Antibody responses to Plasmodium falciparum: evolution according to the severity of a prior clinical episode and association with subsequent reinfection.

We measured sporozoite- and total parasite antigen-specific IgG and IgM antibodies before and after treatment in matched groups of Gabonese children who presented with either mild or severe Plasmodium falciparum malaria. We investigated the influence of various parameters on these antibody responses, including clinical presentation, age, and post-treatment reinfection profiles. IgG but not IgM responses were strongly influenced by both clinical and parasitological status. IgG responses to the repeat region of the circumsporozoite protein, which were low at admission, particularly so in those with severe anemia, increased after treatment but showed no association with either age or reinfection profiles. Total parasite antigen-specific IgG responses were strongly influenced by parasitological status, and also differed significantly when segregated according to clinical status at admission, age, and reinfection histories. Most notably, anti-parasite IgG responses measured when children were parasite-free were higher and a good indicator of recent reinfections in those who presented with mild rather than with severe malaria. The profile of responses in the latter group suggests some immune system dysfunction, which may reflect the induction of tolerance to parasite antigens.

Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children.

The contribution of T cell-mediated responses was studied with regard to resistance to reinfection in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. In those admitted with mild malaria, but not in those with severe malaria, production of IFN-gamma by peripheral blood mononuclear cells (PBMC) in response to either liver-stage or merozoite antigen peptides was associated with significantly delayed first reinfections and with significantly lower rates of reinfection. Proliferative or tumor necrosis factor responses to the same peptides showed no such associations. Production of interferon-gamma by PBMC in response to sporozoite and merozoite antigen peptides was observed in a higher proportion of those presenting with mild malaria. Differences in the Th1/Th2 cytokine balance may be linked to the ability to control parasite multiplication in these young children, helping to explain the marked differences observed in both susceptibility to infection as well as in clinical presentation.

The role of red blood cell polymorphisms in resistance and susceptibility to malaria.

In regions highly endemic for Plasmodium falciparum malaria, red cell polymorphisms that confer resistance to severe disease are widespread. Sickle cell trait, alpha-thalassemia, glucose-6-phosphate dehydrogenase deficiency, and blood groups were determined in 100 children from Gabon with severe malaria who were matched with 100 children with mild malaria and followed up for evaluation of reinfections. The sickle cell trait was significantly associated with mild malaria and blood group A with severe malaria. During follow-up, the original severe cases had significantly higher rates of reinfection than the original mild cases, with higher parasitemia and lower hematocrit values. Incidence rates did not differ in the context of erythrocyte polymorphisms, but patients with sickle cell trait presented with markedly lower levels of parasitemia than those without. Thus, the severity of malaria is partly determined by the presence of blood group A and the sickle cell trait. The different presentation of reinfections in severe versus mild cases probably reflects different susceptibility to malaria.

No influence of socioeconomic factors on severe malarial anaemia, hyperparasitaemia or reinfection.

Malaria is responsible for nearly 500 million clinical cases per year, only a small proportion of whom will become severely ill. Socioeconomic risk factors may play a role in the development of severe malaria in African children and in their susceptibility to reinfection. In Gabon, 100 children suffering from severe malaria, defined as hyperparasitaemia and/or severe anaemia, were matched for sex, age and provenance to 100 children with mild malaria. Socioeconomic factors were assessed using a standard questionnaire and compared between the 2 groups. The children were followed-up and the time to first reinfection was recorded. No significant influence of socioeconomic factors could be detected on the severity of disease or the time to first reinfection. Socioeconomic factors are not major determinants of severe malarial anaemia and hyperparasitaemia in children in Gabon.

Parasite antigen-specific interleukin-10 and antibody reponses predict accelerated parasite clearance in Plasmodium falciparum malaria.

Using strict inclusion criteria, we conducted a hospital-based, case-control study in which 100 Gabonese children with severe Plasmodium falciparum malaria were matched for age, gender and provenance with 100 children presenting with mild malaria. Parasite antigen-specific cellular and humoral immunological responses were measured and compared with post-treatment parasite clearance times in each group. Significantly faster parasite clearance times were associated with in vitro production of IL-10 by acute-phase peripheral blood mononuclear cells (PBMC) in response to both liver and asexual stage parasite antigens, but not with proliferative, IFN-gamma, or TNF responses to the same antigens. In addition, in those children with mild malaria, higher levels of acute-phase antibody responses to liver stage antigen-1 (LSA-1) were associated with faster parasite clearance times, and were correlated with the presence of IL-10 responses to the same antigen. No such associations were found for IL-10 or antibody responses to a range of asexual blood stage antigens. Those with severe malaria had significantly lower levels of anti-LSA-1 antibodies compared to their counterparts with mild malaria. In conclusion, the results of this study suggest that parasite antigen-specific IL-10-mediated antibody responses may play a role in the control of asexual stage parasite multiplication in P. falciparum malaria.