Malaria im Kindesalter: Beiträge zu Prävention und Behandlung

Malaria bleibt eine global bedeutende parasitäre Infektionskrankheit. Malaria-bedingte Morbidität und Mortalität betreffen vorallem junge Kinder. Präventive Maßnahmen sowie erfolgreiches Fallmanagement stellen Säulen bei den Eindämmungsbestrebungen der Malaria dar. Einem effektiven Malariaimpfstoff wird ein entscheidender Beitrag bei der Reduktion von Malaria-bedingter Krankheitslast und Sterblichkeit zugeschrieben. Der Malariaimpfstoffkandidat GMZ2 zeigte in einer pädiatrischen Phase I randomisiert kontrollierten Studie in Gabun eine gute Verträglichkeit, Sicherheit und Immunogenität. Eine reduzierte Antikörperantwort war mit einer Trichuris trichiura Infektion assoziiert. Die Ergebnisse dieser Studie bestätigten vorausgehende klinische Prüfungen von GMZ2 bei Erwachsenen und erlaubten die Fortführung der klinischen Prüfung von GMZ2 in einer Phase II Studie. Die Artemisinin-basierte Therapie ist heute Standardmalariatherapie. Artesunat/Pyronaridin, eine neue Artemisininkombinationstherapie, zeigte in einer pädiatrischen Phase II Dosisfindungsstudie in Gabun in allen Dosierungsgruppen sowie in Tabletten- als auch pädiatrischer Granulatdarreichungsform hohe Wirksamkeit, gute Verträglichkeit und Sicherheit. Die Ergebnisse dieser Studie erlaubten die Fortsetzung der klinischen Entwicklung von Artesunat/Pyronaridin. In einer ersten prospektiven Prüfung von Artemether/Lumefantrin für Non-Falciparum Malaria zeigte Artemether/Lumefantrin bei pädiatrischen und erwachsenen Patienten in Gabun mit P. malariae, P. ovale und Malariamischinfektionen eine hohe Heilungsrate sowie gute Sicherheit und Verträglichkeit. Die Daten dieser Studie unterstützten die gängige Praxis Blutstadien der Non-Falciparum Malaria mit Artemether/Lumefantrin zu behandeln. Pädiatrische Darreichungsformen Artemisinin-basierter Kombinationstherapie wurden entwickelt um die ambulante Therapie junger Kinder mit Malaria zu verbessern. Die systematische Übersichtsarbeit zeigte keinen Unterschied für Therapieversagen oder Sicherheit zwischen pädiatrischen und nicht-pädiatrischen Darreichungsformen. Kinder die lösliche pädiatrische Tabletten erhielten erlitten weniger Medikamenten-assoziierte unerwünsche Nebenwirkungen; pädiatrische lösliche Tabletten waren damit besser verträglich. Erstlinienempfehlung der Weltgesundheitsorganisation für die Therapie der schweren Malaria ist die Therapie mit intravenösem Artesunat. Der standardmäßige Einsatz von intravenösem Artesunat bei schwerer importierter Malaria ist jedoch aufgrund mangelnder Evidenz für Nichtendemiegebiete und fehlender Zulassung teilweise noch limitiert. Die retrospektive Studie zu intravenöser Artesunattherapie bei Kindern mit schwerer importierter Malaria in Deutschland zeigte eine hohe Wirksamkeit und unterstützt somit den Einsatz von intravenösem Artesunat bei importierter schwerer Malaria bei Kindern. Die vorliegende Arbeit umfasst mehrere Beiträge zur Prävention und Behandlung der Malaria im Kindesalter

New imaging approaches for improving diagnosis of childhood tuberculosis

In South Africa (SA), childhood tuberculosis (TB) still accounts for considerable morbidity and mortality. The incidence of TB disease and risk of progression to severe or disseminated forms are especially high in young children or those with HIV infection. Childhood TB presents most commonly as primary TB, often with non specific signs and symptoms; TB may also present as acute pneumonia. The clinical diagnosis can therefore be challenging. Furthermore, due to difficulty in obtaining good-quality specimens and the paucibacillary nature of childhood TB, microbiological confirmation is only achieved in a minority of children, especially in settings where there is limited capacity for microbiological confirmation

Impact of Anti-Retroviral Treatment and Cotrimoxazole Prophylaxis on Helminth Infections in HIV-Infected Patients in Lambar�n�, Gabon

Background: Foci of the HIV epidemic and helminthic infections largely overlap geographically. Treatment options for helminth infections are limited, and there is a paucity of drug-development research in this area. Limited evidence suggests that antiretroviral therapy (ART) reduces prevalence of helminth infections in HIV-infected individuals. We investigated whether ART exposure and cotrimoxazole preventive therapy (CTX-P) is associated with a reduced prevalence of helminth infections. Methodology and Principal Findings: This cross-sectional study was conducted at a primary HIV-clinic in Lambaréné, Gabon. HIV-infected adults who were ART-naïve or exposed to ART for at least 3 months submitted one blood sample and stool and urine samples on 3 consecutive days. Outcome was helminth infection with intestinal helminths, Schistosoma haematobium, Loa loa or Mansonella perstans. Multivariable logistic regression was used to assess associations between ART or CTX-P and helminth infection. In total, 408 patients were enrolled. Helminth infection was common (77/252 [30.5%]). Filarial infections were most prevalent (55/310 [17.7%]), followed by infection with intestinal helminths (35/296 [11.8%]) and S. haematobium (19/323 [5.9%]). Patients on CTX-P had a reduced risk of Loa loa microfilaremia (adjusted odds ratio (aOR) 0.47, 95% CI 0.23-0.97, P = 0.04), also in the subgroup of patients on ART (aOR 0.36, 95% CI 0.13-0.96, P = 0.04). There was no effect of ART exposure on helminth infection prevalence. Conclusions/Significance: CTX-P use was associated with a decreased risk of Loa loa infection, suggesting an anthelminthic effect of antifolate drugs. No relation between ART use and helminth infections was established

Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon

Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. Trial Registration: ClinicalTrials.gov Identifier: NCT0072577

Barriers and facilitators to the uptake of tuberculosis diagnostic and treatment services by hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review of qualitative literature

Summary Tuberculosis disproportionately affects hard-to-reach populations, such as homeless people, migrants, refugees, prisoners, or drug users. These people often face challenges in accessing quality health care. We did a systematic review of the qualitative literature to identify barriers and facilitators to the uptake of tuberculosis diagnostic and treatment services by people from hard-to-reach populations in all European Union (EU), European Economic Area, EU candidate, and Organisation for Economic Co-operation and Development countries. The 12 studies included in this review mainly focused on migrants. Views on perceived susceptibility to and severity of tuberculosis varied widely and included many misconceptions. Stigma and challenges regarding access to health care were identified as barriers to tuberculosis diagnosis and treatment uptake, whereas support from nurses, family, and friends was a facilitator for treatment adherence. Further studies are required to identify barriers and facilitators to the improved identification and management of tuberculosis in hard-to-reach populations to inform recommendations for more effective tuberculosis control programmes

Effectiveness of interventions for diagnosis and treatment of tuberculosis in hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review

Tuberculosis is over-represented in hard-to-reach (underserved) populations in high-income countries of low tuberculosis incidence. The mainstay of tuberculosis care is early detection of active tuberculosis (case finding), contact tracing, and treatment completion. We did a systematic review with a scoping component of relevant studies published between 1990 and 2015 to update and extend previous National Institute for Health and Care Excellence (NICE) reviews on the effectiveness of interventions for identifying and managing tuberculosis in hard-to-reach populations. The analyses showed that tuberculosis screening by (mobile) chest radiography improved screening coverage and tuberculosis identification, reduced diagnostic delay, and was cost-effective among several hard-to-reach populations. Sputum culture for pre-migration screening and active referral to a tuberculosis clinic improved identification. Furthermore, monetary incentives improved tuberculosis identification and management among drug users and homeless people. Enhanced case management, good cooperation between services, and directly observed therapy improved treatment outcome and compliance. Strong conclusions cannot be drawn because of the heterogeneity of evidence with regard to study population, methodology, and quality

Adolescence As Risk Factor for Adverse Pregnancy Outcome in Central Africa – A Cross-Sectional Study

BACKGROUND: Sub-Saharan Africa has the highest rates of maternal and neonatal mortality worldwide. Young maternal age at delivery has been proposed as risk factor for adverse pregnancy outcome, yet there is insufficient data from Sub-Saharan Africa. The present study aimed to investigate the influence of maternal adolescence on pregnancy outcomes in the Central African country Gabon. METHODOLOGY AND PRINCIPAL FINDINGS: Data on maternal age, parity, birth weight, gestational age, maternal Plasmodium falciparum infection, use of bednets, and intake of intermittent preventive treatment of malaria in pregnancy were collected in a cross-sectional survey in 775 women giving birth in three mother-child health centers in Gabon. Adolescent women (≤16 years of age) had a significantly increased risk to deliver a baby with low birth weight in univariable analysis (22.8%, 13/57, vs. 9.3%, 67/718, OR: 2.9, 95% CI: 1.5-5.6) and young maternal age showed a statistically significant association with the risk for low birth weight in multivariable regression analysis after correction for established risk factors (OR: 2.7; 95% CI: 1.1-6.5). In further analysis adolescent women were shown to attend significantly less antenatal care visits than adult mothers (3.3±1.9 versus 4.4±1.9 mean visits, p<0.01, n = 356) and this difference accounted at least for part of the excess risk for low birth weight in adolescents. CONCLUSION: Our data demonstrate the importance of adolescent age as risk factor for adverse pregnancy outcome. Antenatal care programs specifically tailored for the needs of adolescents may be necessary to improve the frequency of antenatal care visits and pregnancy outcomes in this risk group in Central Africa

A Randomized Controlled Phase Ib Trial of the Malaria Vaccine Candidate GMZ2 in African Children

BACKGROUND: GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials. METHODOLOGY/PRINCIPAL FINDINGS: Thirty children one to five years of age were randomized to receive three doses of either 30 µg or 100 µg of GMZ2, or rabies vaccine. GMZ2, adjuvanted in aluminum hydroxide, was administered on Days 0, 28 and 56. All participants received a full course of their respective vaccination and were followed up for one year. Both 30 µg and 100 µg GMZ2 vaccine doses were well tolerated and induced antibodies and memory B-cells against GMZ2 as well as its antigenic constituents MSP3 and GLURP. After three doses of vaccine, the geometric mean concentration of antibodies to GMZ2 was 19-fold (95%CI: 11,34) higher in the 30 µg GMZ2 group than in the rabies vaccine controls, and 16-fold (7,36) higher in the 100 µg GMZ2 group than the rabies group. Geometric mean concentration of antibodies to MSP3 was 2.7-fold (1.6,4.6) higher in the 30 µg group than in the rabies group and 3.8-fold (1.5,9.6) higher in the 100 µg group. Memory B-cells against GMZ2 developed in both GMZ2 vaccinated groups. CONCLUSIONS/SIGNIFICANCE: Both 30 µg as well as 100 µg intramuscular GMZ2 are immunogenic, well tolerated, and safe in young, malaria-exposed Gabonese children. This result confirms previous findings in naïve and malaria-exposed adults and supports further clinical development of GMZ2. TRIAL REGISTRATION: ClinicalTrials.gov NCT00703066