Klaus Reither

Intermittent Preventive Treatment in Infants as a Means of Malaria Control: a Randomized, Double-Blind, Placebo-Controlled Trial in Northern Ghana

ABSTRACT Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 months of age to assess morbidity and adverse events. During the intervention period (3 to 18 months of age), IPTi reduced the incidences of malaria and severe anemia by 22.5% (95% confidence interval, 12 to 32%) and 23.6% (95% confidence interval, 4 to 39%), respectively, and reduced hospitalizations and episodes of asymptomatic parasitemia by one-third. Protection was pronounced in the first year of life and not discernible in the second. The malaria-protective effect was largely confined to a period of 1 month after sulfadoxine-pyrimethamine treatments. Following the intervention, protection against asymptomatic parasitemia persisted. In contrast, a significant rebound of severe malaria, predominantly severe malarial anemia, occurred among children having received IPTi. Although the treatment was generally well tolerated, one case of moderately severe skin reaction followed sulfadoxine-pyrimethamine treatment. IPTi reduces malaria and anemia in infants in northern Ghana. Extension of IPTi into the second year of life by administering a dose at 15 months of age provided no substantial benefit beyond a 1-month prophylactic effect. Although this simple intervention offers one of the few available malaria-preventive measures for regions where malaria is endemic, the observed rebound of severe malaria advises caution and requires further investigation.

MR-guided interstitial laser-induced thermotherapy of hepatic metastasis combined with arterial blood flow reduction: technique and first clinical results in an open MR system.

The feasibility and safety of percutaneous laser‐induced thermotherapy (LITT) of liver metastases in an open low‐field magnetic resonance imaging (MRI) system combined with microsphere‐modulated blood flow reduction were tested. Nd:YAG laser therapy with an internally cooled laser applicator was performed under local anesthesia on 20 patients with 34 liver metastases. To increase the effectivenes of LITT, degradable starch microspheres were injected into the proper hepatic artery through an MR‐visible catheter initially inserted under fluoroscopy. Near real‐time imaging was used for positioning the laser applicator. A T1‐weighted gradient‐echo breath‐hold sequence was used for catheter localization and temperature monitoring. The volumes of the liver metastases and the thermonecroses were determined. MRI‐guided LITT could be performed in all patients with no clinically relevant complications. Intraprocedural imaging underestimated the extent of thermonecrosis. In conclusion, percutaneous LITT of liver metastases after injection of starch microspheres is both technically feasible and safe in an open MRI system. J. Magn. Reson. Imaging 2001;13:31–36.

Magnetic resonance-guided vascular catheterization: feasibility using a passive tracking technique at 0.2 Telsa in a pig model.

The objective of this study was to demonstrate in an animal model the feasibility of a passive tracking technique for catheter visualization of magnetic resonance (MR)‐guided endovascular procedures. All experiments were performed in a 0.2 Tesla open MR system. Susceptibility‐based catheters and guide wires were introduced into the aorta and were advanced selectively into the splenic and renal arteries under MR guidance. Based on a previously acquired contrast‐enhanced magnetic resonance angiography (MRA) data set, the catheter positioning was performed by using a single‐slice true fast imaging with steady state precession (FISP) sequence with a frame rate of 1.3 seconds. Contrast‐enhanced MRA was performed in all animals. All catheters were advanced without complications into the aorta and were introduced into the proximal parts of the right renal and splenic arteries under MR guidance. Catheter manipulations were more difficult in the distal parts of these vessels due to the more complex anatomy. Passive catheter tracking is a valuable and technically robust alternative to active tracking methods, because it does not require additional hardware and, thus, can be implemented and used easily with any open MR imaging system. J. Magn. Reson. Imaging 1999;10:841–844.

Blood or urine IP-10 cannot discriminate between active tuberculosis and respiratory diseases different from tuberculosis in children

Objectives. Interferon-γ inducible protein 10 (IP-10), either in blood or in urine, has been proposed as a tuberculosis (TB) biomarker for adults. This study aims to evaluate the potential of IP-10 diagnostics in children from Uganda, a high TB-endemic country. Methods. IP-10 was measured in the blood and urine concomitantly taken from children who were prospectively enrolled with suspected active TB, with or without HIV infection. Clinical/microbiological parameters and commercially available TB-immune assays (tuberculin skin test (TST) and QuantiFERON TB-Gold In-Tube (QFT-IT)) were concomitantly evaluated. Results. One hundred twenty-eight children were prospectively enrolled. The analysis was performed on 111 children: 80 (72%) of them were HIV-uninfected and 31 (27.9%) were HIV-infected. Thirty-three healthy adult donors (HAD) were included as controls. The data showed that IP-10 is detectable in the urine and blood of children with active TB, independent of HIV status and age. However, although IP-10 levels were higher in active TB children compared to HAD, the accuracy of identifying “active TB” was low and similar to the TST and QFT-IT. Conclusion. IP-10 levels are higher in children with respiratory illness compared to controls, independent of “TB status” suggesting that the evaluation of this parameter can be used as an inflammatory marker more than a TB test.

Field Evaluation of a Rota- and Adenovirus Immunochromatographic Assay Using Stool Samples from Children with Acute Diarrhea in Ghana

ABSTRACT We evaluated the Rida Quick rotavirus/adenovirus Combi rapid immunochromatographic test (ICT) under field conditions with Ghanaian children with acute diarrhea. Compared to PCR results, sensitivities and specificities were 75% and 95% for rotavirus and 22% and 84% for adenovirus. In resource-poor settings, ICTs may help to overcome difficulties in the diagnosis of rotavirus infection.

Low contrast dose voiding urosonography in children with phase inversion imaging

Voiding urosonography (VUS) using a microbubble contrast agent has been introduced as an alternative technique in the diagnosis of vesicoureteral reflux (VUR). This study was undertaken to assess if phase inversion ultrasound (PIUS), a recent microbubble specific imaging technique, has advantages over fundamental in VUS and if it allows a reduction of contrast agent dose. Forty-three children with suspected VUR (aged 3 days–12 years, average of 3.9 years) with 92 kidney-ureter units (KUU) were included. Everyone obtained a baseline US scan that was followed by VUS using Levovist as the contrast agent. Constant switching between fundamental and PIUS performed the enhanced part for comparison. Every child underwent VCUG immediately afterwards. Contrast enhancement was stronger and longer lasting on PIUS than on fundamental US in all 43 cases. Reflux was detected in a total of 21 KUU, out of 92 KUU (23%). PIUS revealed VUR in 18; fundamental in 14 KUU and VCUG depicted 16 cases of reflux (p≥0.29). The mean volume of Levovist dose administered to the bladder was 7.4±3.4% of the bladder volume. VUS using PI mode provided considerably stronger and longer enhancement and slightly improved the detection of VUR. It allowed a reduction of contrast dose and cost by approximately 35% over current dose recommendations for fundamental US.

Reduced Efficacy of Intermittent Preventive Treatment of Malaria in Malnourished Children

ABSTRACT Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], −7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.

Detection of Mycobacterium tuberculosis by EasyNAT Diagnostic Kit in Sputum Samples from Tanzania

ABSTRACT The EasyNAT assay was evaluated for the detection of tuberculosis in sputum smears from presumptive pulmonary tuberculosis (TB) patients in an African high-TB and high-HIV setting. The sensitivity of the EasyNAT assay was 66.7%, and the specificity and positive predictive value were 100% for the culture-positive patients. The sensitivity was only 10% in the smear-negative and culture-positive patients.

Multiplicity of Plasmodium falciparum infection following intermittent preventive treatment in infants

BackgroundIntermittent preventive treatment in infants with sulphadoxine-pyrimethamine (IPTi-SP) reduces malaria morbidity by 20% to 33%. Potentially, however, this intervention may compromise the acquisition of immunity, including the tolerance towards multiple infections with Plasmodium falciparum.MethodsPlasmodium falciparum isolates were obtained from children participating in two Ghanaian IPTi-SP trials (Tamale, Afigya Sekyere) at 15 months of age, i.e., six months after they had received the second dose of IPTi-SP or placebo. By typing the polymorphic merozoite surface protein 1 (msp1) and msp2 genes, multiplicity of infection (MOI) was assessed in 389 isolates. A total of additional 133 samples were collected in Tamale at 3, 6, 9, and 12 months of age. Comparisons of MOI between groups were done by non-parametric statistical tests.ResultsThe number of distinguishable P. falciparum clones (MOI) ranged between one and six. Mean MOI in Tamale was stable at 2.13 - 2.17 during the first year of life, and increased to 2.57 at age 15 months (P = 0.01). At no age did MOI differ between the IPTi-SP and placebo groups (each, P ≥ 0.5). At 15 months of age, i.e., six months after the second dose, MOI was very similar for children who had received IPTi or placebo (means, 2.25 vs. 2.33; P = 0.55) as was the proportion of polyclonal infections (69.6% vs. 69.7%; P = 0.99). Adjusting for study site, current and prior malaria, parasite density, and season did not change this finding.ConclusionsIPTi-SP appears to have no impact on the multiplicity of infection during infancy and thereafter. This suggests that tolerance of multiple infections, a component of protective immunity in highly endemic areas, is not affected by this intervention.

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

Background Human tuberculosis (TB) is caused by seven phylogenetic lineages of the Mycobacterium tuberculosis complex (MTBC), Lineage 1–7. Recent advances in rapid genotyping of MTBC based on single nucleotide polymorphisms (SNP), allow for rapid and phylogenetically robust strain classification, paving the way for defining genotype-phenotype relationships in clinical settings. Such studies have revealed that, in addition to host and environmental factors, different strains of the MTBC influence the outcome of TB infection and disease. In Tanzania, such molecular epidemiological studies of TB however are scarce in spite of a high TB burden. Methods and Findings Here we used a SNP-typing method to genotype a nationwide collection of 2,039 MTBC clinical isolates obtained from new and retreatment TB cases diagnosed in 2012 and 2013. Four lineages, namely Lineage 1–4 were identified. The distribution and frequency of these lineages varied across the regions but overall, Lineage 4 was the most frequent (n=866, 42.5%), followed by Lineage 3 (n=681, 33.4%) and 1 (n=336, 16.5%), with Lineage 2 being the least frequent (n=92, 4.5%). A total of 64 (3.1%) isolates could not be assigned to any lineage. We found Lineage 2 to be associated with female sex (adjusted odds ratio [aOR] 2.25; 95% confidence interval [95% CI] 1.38 – 3.70, p<0.001) and retreatment (aOR 1.78; 95% CI 1.00 – 3.02, p=0.040). We found no associations between MTBC lineage and patient age or HIV status. Our sublineage typing based on spacer oligotyping revealed the presence of mainly EAI, CAS and LAM families. Finally, we detected low levels of multidrug resistant isolates among a subset of retreatment cases Conclusions This study provides novel insights into the influence of pathogen-related factors on the TB epidemic in Tanzania.