Where is the 'C' in antenatal care and postnatal care: A multi-country survey of availability of antenatal and postnatal care in low- and middle-income settings.

OBJECTIVE: Antenatal (ANC) and postnatal care (PNC) are logical entry points for prevention and treatment of pregnancy-related illness and to reduce perinatal mortality. We developed signal functions and assessed availability of the essential components of care. DESIGN: Cross-sectional survey. SETTING: Afghanistan, Chad, Ghana, Tanzania, Togo. SAMPLE: Three hundred and twenty-one healthcare facilities. METHODS: Fifteen essential components or signal functions of ANC and PNC were identified. Healthcare facility assessment for availability of each component, human resources, equipment, drugs and consumables required to provide each component. MAIN OUTCOME MEASURE: Availability of ANC PNC components. RESULTS: Across all countries, healthcare providers are available (median number per facility: 8; interquartile range [IQR] 3-17) with a ratio of 3:1 for secondary versus primary care. Significantly more women attend for ANC than PNC (1668 versus 300 per facility/year). None of the healthcare facilities was able to provide all 15 essential components of ANC and PNC. The majority (>75%) could provide five components: diagnosis and management of syphilis, vaccination to prevent tetanus, BMI assessment, gestational diabetes screening, monitoring newborn growth. In Sub-Saharan countries, interventions for malaria and HIV (including prevention of mother to child transmission [PMTCT]) were available in 11.7-86.5% of facilities. Prevention and management of TB; assessment of pre- or post-term birth, fetal wellbeing, detection of multiple pregnancy, abnormal lie and presentation; screening and support for mental health and domestic abuse were provided in <25% of facilities. CONCLUSIONS: Essential components of ANC and PNC are not in place. Focused attention on content is required if perinatal mortality and maternal morbidity during and after pregnancy are to be reduced. TWEETABLE ABSTRACT: ANC and PNC are essential care bundles. We identified 15 core components. These are not in place in the majority of LMIC settings.

Cytokine and chemokine responses to helminth and protozoan parasites and to fungus and mite allergens in neonates, children, adults, and the elderly.

BACKGROUND: In rural sub-Saharan Africa, endemic populations are often infected concurrently with several intestinal and intravascular helminth and protozoan parasites. A specific, balanced and, to an extent, protective immunity will develop over time in response to repeated parasite encounters, with immune responses initially being poorly adapted and non-protective. The cellular production of pro-inflammatory and regulatory cytokines and chemokines in response to helminth, protozoan antigens and ubiquitous allergens were studied in neonates, children, adults and the elderly. RESULTS: In children schistosomiasis prevailed (33%) while hookworm and Entamoeba histolytica/E. dispar was found in up to half of adults and the elderly. Mansonella perstans filariasis was only present in adults (24%) and the elderly (25%). Two or more parasite infections were diagnosed in 41% of children, while such polyparasitism was present in 34% and 38% of adults and the elderly. Cytokine and chemokine production was distinctively inducible by parasite antigens; pro-inflammatory Th2-type cytokine IL-19 was activated by Entamoeba and Ascaris antigens, being low in neonates and children while IL-19 production enhanced "stepwise" in adults and elderly. In contrast, highest production of MIP-1delta/CCL15 was present in neonates and children and inducible by Entamoeba-specific antigens only. Adults and the elderly had enhanced regulatory IL-27 cytokine responses, with Th2-type chemokines (MCP-4/CCL13, Eotaxin-2/CCL24) and cytokines (IL-33) being notably inducible by helminth- and Entamoeba-specific antigens and fungus-derived allergens. The lower cellular responsiveness in neonates and children highlighted the development of a parasite-specific cellular response profile in response to repeated episodes of exposure and re-infection. CONCLUSIONS: Following repeated exposure to parasites, and as a consequence of host inability to prevent or eliminate intestinal helminth or protozoa infections, a repertoire of immune responses will evolve with lessened pro-inflammatory and pronounced regulatory cytokines and chemokines; this is required for partial parasite control as well as for preventing inadequate and excessive host tissue and organ damage.

Cytokine and chemokine responses in adults, newborns and children exposed to Entamoeba histolytica/dispar, Onchocerca volvulus and Plasmodium falciparum.

Cytokine and chemokine response profiles were studied in newborns, 10-yr-old children and post partum mothers. All study groups were repeatedly exposed to Entamoeba histolytica, Onchocerca volvulus and Plasmodium falciparum infections as indicated by their Immunoglobulin (IgG) responses to parasite-specific antigens. As key indicators for regulatory and pro-inflammatory cytokine and chemokine responses, Interferon (IFN)gamma and regulatory IL-10 were investigated, along with the chemokines MIP-1 alpha/CCL3, MIP-1 beta/CCL4, MDC/CCL22 and TARC/CCL17. Entamoeba histolytica antigens (EhAg) strongly activated pro-inflammatory MIP-1 alpha/CCL3 and MIP-1 beta/CCL4 responses of similar magnitude in mothers, children and neonates alike. Plasmodium falciparum antigens (PfAg) enhanced MIP-1 alpha/CCL3, MIP-1 beta/CCL4 and MDC/CCL22 production in neonates, but did not trigger these chemokines in mothers or 10-yr-old children. Onchocerca volvulus antigens (OvAg) activated IFN-gamma and TARC/CCL17 production in mothers but not in neonates and children. Crude IL-10 production [i.e., without subtracting spontaneous cellular release (baseline)] was highest in mothers and somewhat lower in neonates, while the lowest IL-10 amounts of all were released by peripheral blood mononuclear cells from 10-yr-old children. In summary, strong inflammatory chemokine responses to plasmodia and ameba antigens in newborns and 10-yr-old children suggest that adequately balanced immune regulatory mechanisms may not have developed yet in these age groups and that repeated exposure to parasite infections and immune maturation during childhood is required to generate similar cytokine and chemokine profiles as in adults.

Cellular gene expression induced by parasite antigens and allergens in neonates from parasite-infected mothers.

Prenatal exposure to parasite antigens or allergens will influence the profile and strength of postnatal immune responses, such contact may tolerize and increase susceptibility to future infections or sensitize to environmental allergens. Exposure in utero to parasite antigens will distinctly alter cellular gene expression in newborns. Gene microarrays were applied to study gene expression in umbilical cord blood cell (UCBC) from parasite-exposed (Para-POS) and non-exposed (Para-NEG) neonates. UCBC were activated with antigens of helminth (Onchocerca volvulus), amoeba (Entamoeba histolytica) or allergens of mite (Dermatophagoides farinae). When UCBC from Para-POS and Para-NEG newborns were exposed to helminth antigens or allergens consistent differences occurred in the expression of genes encoding for MHC class I and II alleles, signal transducers of activation and transcription (STATs), cytokines, chemokines, immunoglobulin heavy and light chains, and molecules associated with immune regulation (SOCS, TLR, TGF), inflammation (TNF, CCR) and apoptosis (CASP). Expression of genes associated with innate immune responses were enhanced in Para-NEG, while in Para-POS, the expression of MHC class II and STAT genes was reduced. Within functional gene networks for cellular growth, proliferation and immune responses, Para-NEG neonates presented with significantly higher expression values than Para-POS. In Para-NEG newborns, the gene cluster and pathway analyses suggested that gene expression profiles may predispose for the development of immunological, hematological and dermatological disorders upon postnatal helminth parasite infection or allergen exposure. Thus, prenatal parasite contact will sensitize without generating aberrant inflammatory immune responses, and increased pro-inflammatory but decreased regulatory gene expression profiles will be present in those neonates lacking prenatal parasite antigen encounter.

Applied field research for comprehensive helminth infection control.

The Institute for Tropical Medicine at University of Tübingen has established 30 years ago in Togo a Research Centre and Onchocerciasis Reference Laboratory (ORL). Onchocerca volvulus infection control and of other neglected tropical diseases has been the focus of activities, and those were performed together with the National Institute of Hygiene in Togo, the Medical Faculty at University of Lomé, national disease control programs and district and regional hospitals. The ORL contributed significantly to the assessment of ivermectin as the prime choice for onchocerciasis treatment, and 24 years of repeated annual treatment with ivermectin has progressively reduced disease prevalence and notably the level of ocular and dermal manifestations of onchocerciasis in the endemic population. The ORL has shown that large parts of the rural population in Togo is concurrently infected with intestinal and intravascular protozoan and helminth parasites, notably school children. The application of repeated treatments with albendazole and praziquantel against Schistosoma spp. and instestinal helminthes for several years has reduced infection intensities by more than 80%. Longitudinal investigations of the cellular immune responses in adults and children have found that parasite co-infections will generate prominent pro-inflammatory responses, and a single or few interventions will not suffice to eliminate co-infections and not establish an appropriately balanced immunity.

Coinfections with Schistosoma haematobium, Necator americanus, and Entamoeba histolytica/Entamoeba dispar in children: chemokine and cytokine responses and changes after antiparasite treatment.

The effect of polyparasite infections on cytokine and chemokine responses as well as the effect of antiparasite treatment was studied in children without parasite infection (the G0 group), in children singly infected with Schistosoma haematobium (the G1 group), and in children multiply infected with S. haematobium/Schistosoma mansoni, Entamoeba histolytica/Entamoeba dispar, and Necator americanus (the G3+ group). Linear regression analysis disclosed a significant risk for coinfection with hookworm and Schistosoma species. Polyparasite infections detected in 23% of children before treatment were present in 5% at 15 months after treatment. Chemokine responses to S. mansoni adult worm antigen (SmAg) diminished after treatment for macrophage inflammatory chemokine (MIP)-1alpha/chemokine (C-C motif) ligand (CCL)-3 (among G3+ children, by a factor of 200 [95% confidence interval {CI}, 33-1111]) and for MIP-1beta/CCL-4 (among G3+ children, by a factor of 26 [95% CI, 6-117]) but were enhanced for thymus- and activation-regulated chemokine/CCL-17 (among G3+ children, by a factor of 10 [95% CI, 3-32]) (P < .001 for all). In response to E. histolytica antigen, interleukin (IL)-13 levels increased after treatment among G1 children by a factor of 138 (95% CI, 12-1569) and among G3+ children by a factor of 21 (95% CI, 7-64) (P < .001 for both). Cellular production of interferon (IFN)-gamma in response to SmAg decreased 4 weeks after treatment among G3+ children, whereas T helper cell type 2 (Th2) IL-13 production was enhanced among G1 and G3+ children. In summary, polyparasite infections with S. haematobium/S. mansoni, E. histolytica/E. dispar, and N. americanus generated prominent proinflammatory cytokine and chemokine responses, and, after antihelminth treatment, the inflammatory chemokine response lessened as the Th2 responsiveness in coinfected children increased.

Parasite-specific antibody and cytokine profiles in newborns from Plasmodium falciparum and Entamoeba histolytica/dispar-infected mothers.

Passage of parasites and their antigens across the placenta occurs with metazoan as well as protozoan parasites, and this study addressed to which extent exposure to and infection of mothers with Plasmodium spp. and Entamoeba histolytica/dispar has sensitized their offspring for parasite-specific immune responses. While at delivery none of the mothers presented with an acute malaria attack, 42% were seropositive for P. falciparum. In half of the mothers cysts of E. histolytica/dispar were detected in stool specimen, 51% of them were found seropositive for E. histolytica, and E. histolytica-specific immunoglobulin A (IgA) responses were detected in neonates of seropositive mothers as well. Umbilical cord blood cells (UCBC) from neonates, when activated with the mitogen phytohaemagglutinine (PHA) and bacterial streptolysin O (SL-O), released significantly less interferon (IFN)-gamma, interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha into cell culture supernatants than peripheral blood cells (PBMC) of mothers. In response to Plasmodium- and Entamoeba-specific antigens UCBC and PBMC produced equal amounts of IL-1beta, TNF-alpha, IFN-gamma and IL-5, but PBMC from mothers secreted significantly more IL-10. Parasite-specific production of inflammatory and Th(1)- and Th(2)-type cytokines was similar in newborns of Plasmodium and Entamoeba seropositive and seronegative mothers. In summary, repeated exposure and subclinical infection of mothers with E. histolytica or P. falciparum will suffice to prime in utero their children for inflammatory and both Th(1)- and Th(2)-type cytokine responses, and such broad and mixed cytokine spectrum may be of advantage upon secondary parasite challenge in later life.