Preterm birth is a major cause of neonatal mortality and morbidity worldwide. Bacterial infection and the subsequent inflammatory response are recognised as an important cause of preterm birth. It is ...hypothesised that these organisms ascend the cervical canal, colonise placental tissues, cause chorioamnionitis and in severe cases infect amniotic fluid and the foetus. However, the presence of bacteria within the intrauterine cavity does not always precede chorioamnionitis or preterm birth. Whereas previous studies observing the types of bacteria present have been limited in size and the specificity of a few predetermined organisms, in this study we characterised bacteria found in placental tissues from a cohort of 1391 women in rural Malawi using 16S ribosomal RNA gene sequencing. We found that specific bacteria found concurrently on placental tissues associate with chorioamnionitis and delivery of a smaller newborn. Severe chorioamnionitis was associated with a distinct difference in community members, a higher bacterial load and lower species richness. Furthermore, Sneathia sanguinengens and Peptostreptococcus anaerobius found in both matched participant vaginal and placental samples were associated with a lower newborn length-for-age Z-score. This is the largest study to date to examine the placental microbiome and its impact of birth outcomes. Our results provide data on the role of the vaginal microbiome as a source of placental infection as well as the possibility of therapeutic interventions against targeted organisms during pregnancy.
We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no ...other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB.
The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. ...However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.
A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight LBW, <2,500 g, premature birth <37 weeks, still birth >28 weeks, abortion ≤28 weeks, lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 5.0% in the AZCQ group, 68/1188 5.7% in the SP group, RR 0.87 95% CI: 0.62, 1.23; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.
IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.
ClinicalTrials.gov (NCT01103063).
Background. Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, ...radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms. Methods. We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011. Results. We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 38%), followed by opportunistic infections (16 25%). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution–like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001). Conclusions. HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution–like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments.
BackgroundThe sequestration of Plasmodium falciparum–infected erythrocytes in capillary beds is a characteristic feature of severe malaria and is believed to be central to disease pathogenesis. ...Sequestration occurs in all P. falciparum infections, including those in asymptomatic individuals. Therefore, sequestration cannot be the sole determinant of severe disease; the intensity or distribution of infected erythrocytes may also contribute. Discerning the relationship between sequestration and well-defined clinical syndromes may enhance understanding of disease mechanisms MethodsWe measured the concentration of parasite-derived lactate dehydrogenase (pLDH) in tissue samples obtained at autopsy from patients with clinically defined cerebral malaria. On the basis of the autopsy findings, patients were divided into 2 groups: those with an identifiable, nonmalarial cause of death and those without, who were presumed to have died of cerebral malaria. The concentration of pLDH, as determined by enzyme-linked immunosorbent assay, was used to estimate parasite load in different organs ResultsWhen pLDH could be detected, the parasite load was higher in patients with presumed cerebral malaria than in parasitemic patients with assumed cerebral malaria with a nonmalaria cause of death identified at autopsy (P<.05 for brain, intestine, and skin) ConclusionsThese findings suggest that sequestration in patients with fatal cerebral malaria occurs in multiple organs and does not reflect a predilection in the parasite for the cerebral vasculature
Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative ...histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of totalbody parasite sequestration.
CD8
T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. ...Thus, in this study we have provided the first direct contrast of the accumulation of CD8
T cells in the brain during HCM and ECM. HCM cases were from children who died of
cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with
ANKA. We demonstrate similarities in the intracerebral CD8
T cell responses in ECM and HCM, in particular an apparent shared choroid plexus-meningeal route of CD8
T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8
T cells within the cerebrovascular bed in HCM and ECM.
Summary Respiratory signs are common in African children where malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 ...children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum malaria. Our aim was to describe the pathologic manifestations of fatal malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with cerebral malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with cerebral malaria, large numbers of malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with cerebral malaria, noncerebral malaria, and nonmalarial diagnoses. Comorbidities found in some cerebral malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with cerebral malaria does not appear to be anatomic in origin but that increasing malaria pigment is strongly associated with cerebral malaria at autopsy.
Cancer is a leading cause of morbidity and mortality worldwide with a majority of cases and deaths occurring in developing countries. While cancer of the lung, breast, colorectum, stomach and ...prostate are the most common types of cancer globally, in east and southern Africa these are less common and comprehensive data to inform policies are lacking.
Nationwide cancer registry was conducted between September and October 2010 in Malawi. New cancer cases registered from 2007 to 2010 were identified from hospital and clinic registers of 81 out of 84 health facilities providing cancer diagnosis, treatment or palliative care services. Demographic and cancer data were extracted from registers and case notes using a standard form.
A total of 18,946 new cases of cancer were registered in Malawi from 2007-2010. Of these 55.9% were females, 7.2% were children aged less than 15 years, 76.5% were adults aged 15-59 years and 16.4% were elderly aged 60 years or more. Only 17.9% of the cases had histologically verified diagnosis, 33.2% were diagnosed clinically and 49.6% based on clinical and some investigations. Amongst females, cancer of the cervix was the commonest accounting for 45.4% of all cases followed by Kaposi sarcoma (21.1%), cancer of the oesophagus (8.2%), breast (4.6%) and non-Hodgkin lymphoma (4.1%). In males, Kaposi sarcoma was the most frequent (50.7%) then cancer of oesophagus (16.9%), non-Hodgkin lymphoma (7.8), prostate (4.0%) and urinary bladder (3.7%). Age-standardised incidence rate per 100,000 population for all types of cancer in males increased from 31 in 1999-2002 to 56 in 2007-2010. In females it increased from 29 to 69. Kaposi sarcoma and cancer of the oesophagus, cervical cancer and Kaposi sarcoma were the main causes for the increased incidence in males and females respectively. It was estimated that, annually at least 8,151 new cases of cancer (all types) occur in Malawi.
This study provided data on common types and trends of cancer that could be used to focus prevention, treatment and control interventions in the context of limited resources. The problem of under-reporting and misdiagnosis of cancer cases has been highlighted.
Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a ...series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the "classic" appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the "sequestration only" appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without).
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