Effectiveness of incidence thresholds for detection and control of meningococcal meningitis epidemics in northern Togo.

BACKGROUND: Early outbreak detection is necessary for control of meningococcal meningitis epidemics. A weekly incidence of 15 cases per 100 000 inhabitants averaged over 2 consecutive weeks is recommended by the World Health Organization (WHO) for detection of meningitis epidemics in Africa. This and other thresholds are tested for ability to predict outbreaks and timeliness for control measures. METHODS: Meningitis cases recorded for 1990-1997 in health centres of northern Togo were reviewed. Weekly and annual incidences were determined for each district. Ability of different weekly incidence thresholds to detect outbreaks was assessed according to sensitivity, specificity, and positive and negative predictive values. The number of cases potentially prevented by reactive vaccination in 1997 was calculated for each threshold. RESULTS: Outbreaks occurred in 1995-1996 and in 1996-1997. The WHO-recommended threshold had good specificity but low sensitivity. Thresholds of 10 and 7 cases per 100,000 inhabitants in one week had sensitivity and specificity of 100% and increased the time available for intervention by more than one or two weeks, respectively. A maximum of 65% of cases could have been prevented during the 1997 epidemic, with up to 8% fewer cases prevented for each week of delay in achieving vaccine coverage. CONCLUSIONS: In northern Togo, thresholds of 7 or 10 cases per 100,000 inhabitants per week were excellent predictors of meningitis epidemics and allowed more time for a reactive vaccination strategy than current recommendations.

Regulatory effects of Th1-type (IFN-gamma, IL-12) and Th2-type cytokines (IL-10, IL-13) on parasite-specific cellular responsiveness in Onchocerca volvulus-infected humans and exposed endemic controls.

The present study investigated in vitro the regulatory effects of T helper 1 (Th1)-type (interferon-gamma, IFN-gamma; interleukin-12, IL-12) and Th2-type cytokines (IL-10, IL-13) on Onchocerca volvulus-specific cellular reactivity in onchocerciasis patients, and in exposed endemic control individuals presenting no clinical and parasitological signs of disease. In both patients and controls, addition of IL-10 dose-dependently depressed O. volvulus antigen (OvAg)-specific cellular proliferation, and peripheral blood mononuclear cells (PBMC) from patients who were more sensitive to the suppressive effect of IL-10 than those from endemic controls. However, neutralization of IL-10 by specific antibody did not reverse cellular hyporesponsiveness. In contrast to the inhibitory effects of IL-10, exogenous IL-12 and IL-13 augmented PBMC proliferative responses to OvAg both in patients and controls (P<0. 01) and neutralizing of IL-12 or IL-13 significantly decreased OvAg-specific proliferation in both groups. Exogenous IFN-gamma did not activate OvAg-specific proliferative responses in patients, but anti-IFN-gamma antibodies abolished cellular reactivity to OvAg. Antibody to IL-10 increased (P<0.05) OvAg-specific production of IL-5, IL-12 and IFN-gamma, and inversely, anti-IFN-gamma enhanced IL-10 (in patients only) and IL-5 and IL-13 in both patients and controls. Neutralization of IL-12 activated OvAg-specific production of IL-10, IL-2 and IFN-gamma. In conclusion, despite of an overproduction of IL-10, which suppressed cellular reactivity in patients and control individuals, OvAg-specific cellular responses were activated in vitro by exogenous supplementation with IL-12 and IL-13, and cytokine neutralization experiments confirmed that distinct type 1 and type 2 T helper cytokines cross-regulate expression and magnitude of O. volvulus-specific cellular responsiveness in humans.

Prenatal immune priming in onchocerciasis-onchocerca volvulus-specific cellular responsiveness and cytokine production in newborns from infected mothers.

This study investigated the effect of maternal Onchocerca volvulus infection on humoral and cellular responsiveness in newborn children and their mothers. Onchocerca volvulus-specific IgG isotypes and IgE were significantly elevated in infected mothers and their infants. One year post partum, O. volvulus-specific IgG4 was strongly reduced in children of infected mothers, while IgG1 responses weakened only slightly. Umbilical cord mononuclear blood cells (UCBC) and peripheral blood cells (PBMC) from mothers proliferated in response to phytohaemagglutinin (PHA), concanavalin A (Con A), and the bacterial antigens streptolysin-O (SL-O) or purified protein derivative (PPD). UCBC from neonates born to O. volvulus-infected mothers responded lower (P < 0.01) to Con A (at 5 micrograms/ml), PPD (at 10 and 50 micrograms/ml) and O. volvulus-derived antigens (OvAg) (at 35 micrograms/ml), and in parallel, a diminished cellular reactivity (P < 0.01) by PBMC was observed to OvAg in mothers positive for O. volvulus. Several Th1-type (IL-2, IL-12, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)) and Th2-type (IL-4, IL-5, IL-10, IL-13) cytokines were secreted by UCBC and PBMC in response to OvAg, bacterial SL-O and PHA. OvAg did not stimulate IL-2 and none of the mitogens or antigens induced production of IL-4 in neonates. In response to OvAg, substantially elevated (P < 0.01) amounts of IFN-gamma were produced by UCBC from newborns of O. volvulus-infected mothers. UCBC secreted low levels of IL-5 and IL-13, while higher amounts of IL-10 were found (P < 0. 01) in newborns from onchocerciasis-free mothers. In conclusion, maternal O. volvulus-infection will sensitize in utero parasite-specific cellular immune responsiveness in neonates and activate OvAg-specific production of several Th1- and Th2-type cytokines.

The diverse expression of immunity in humans at distinct states of Onchocerca volvulus infection.

This study examined the development and persistence of immunity in humans presenting defined states of Onchocerca volvulus infection, i.e. in exposed endemic control individuals without microfilaridermia and clinical disease, in patients with patent or post-patent onchocerciasis, and in patients concurrently infected with Mansonella perstans. Onchocerca volvulus antigen (OvAg)-specific cellular reactivity was significantly diminished in microfilariae (mf)-positive patients, while the highest reactivity was measured in exposed but mf-negative endemic controls, those being free of any clinical signs of onchocercal disease. In patients who became post-patent, responses to OvAg were significantly augmented, but did not approach entirely the magnitude observed in endemic controls. In onchocerciasis patients with concurrent mansonelliasis, cellular unresponsiveness to OvAg persisted, even when mf of O. volvulus were eliminated permanently by repeated ivermectin therapy. Cells from mf-positive onchocerciasis patients produced significantly less interferon-gamma (IFN-gamma) (P < 0.01) and interleukin-5 (IL-5) (P < 0.05) in response to OvAg than those taken from endemic controls or post-patent individuals in whom IFN-gamma and IL-5 production was similarly high. In contrast, both OvAg-driven as well as spontaneous IL-10 secretion was higher in mf-positive patients than in endemic controls or post-patent cases. In all individuals examined, serological recognition of OvAg by immunoglobulins was dominated by IgG4; in mf-positive patients OvAg of 205,000-12,000 molecular weight (MW) were strongly bound. In post-patent individuals, and similarly in endemic controls. OvAg recognition by IgG4 varied from intense (with numerous antigens being recognized) to weak or absent antigen binding. Significantly elevated OvAg-specific IgG isotypes were measured in mf-positive onchocerciasis patients in comparison with endemic controls or post-patent individuals (with the exception of IgG3). IgG1, IgG2 and IgE were higher, but IgG4 was lower in endemic controls compared with post-patent onchocerciasis patients. The ratios of IgG4/IgG1 differed (P < 0.001) between endemic controls and mf-positive or post-patent onchocerciasis patients, with IgG4/IgG1 ratios of R < 3.0 being characteristic for endemic controls and post-patent O. volvulus infection. In conclusion, this cross-sectional immunoepidemiological investigation showed that distinct states of O. volvulus infection correlate with a particular cellular and humoral immune response. The mf-free condition appeared to be associated with a vigorous parasite-specific cellular reactivity and a particular cytokine production profile, while concurrent M. perstans infection depressed OvAg-specific cellular responsiveness. Antibody responses, in all likelihood, reflected the intensity and state of infection, and not the degree of acquired immunity protective against parasite aggregation.

[An epidemic of meningococcal meningitis in the region of Savanes in Togo in 1997: research and control strategies]. / Une épidémie de méningite à méningocoque dans la région des Savanes au Togo en 1997: investigation et stratégies de contrôle.

Neisseria meningitidis is responsible for high levels of morbidity and mortality in the developing countries of the African meningitis belt. There are frequent meningococcal meningitis epidemics in this region affecting almost 1,000 people in every 100,000 (1%). Epidemics generally occur during the dry season but the interval between epidemics is variable (between 2 and 25 years). The reasons for these recurrent epidemics are unclear. There is a safe and effective polysaccharide vaccine against meningococci A and C. Unfortunately, the immunity it provides decreases with time, especially in young children (aged less than 5 years) and it is thus not included in the Expanded Program on Immunization (EPI). WHO recommends mass vaccination using a threshold approach. This control strategy is effective if vaccination begins very soon after the threshold is crossed. There was an outbreak of group A meningococcal meningitis in the Savanes region of northern Togo in December 1996. The national surveillance system put out an alert and control measures were implemented. These involved improvement of the surveillance system, and containment immunization in villages for early cases followed by a mass immunization campaign in the entire region, distribution of oily chloramphenicol and decentralized case management. The target population for mass vaccination included everyone older than 6 months of age living in the Savanes region. The aim was to vaccinate at least 80% of the target population. There were 2,992 cases of meningitis reported in the Savanes region between December 1996 and May 1997 (in a population of about 500,000). This gives a cumulative incidence rate of 581 per 100,000 population. The epidemic was bimodal, with the first peak in the number of cases occurring at the end of January and the second peak in March. There were 60,700 vaccinations in two of the four districts of the region in December and January, as part of the containment strategy and 346,469 vaccinations in the four districts of the region during February, as part of the mass vaccination campaign. By the end of the mass campaign, 67.3% of the target population in the region as a whole had been vaccinated, with 61% vaccinated in the Kpendjal district and 78% in the Oti district. There was an increase in the number of cases 2 weeks after the end of the mass vaccination campaign. This was attributed to the inadequate level of vaccination achieved. Only 52% of the urban population of Dapaong were vaccinated. The national surveillance system put out an alert early in the epidemic. The intervention was planned and adapted according to the progression of the epidemic, and national and international efforts were well coordinated. This emphasizes the importance of a rapid reaction from the surveillance system and of the choice of strategy for dealing with meningitis epidemics in sub-Sahelian Africa.