Severe malaria in children leads to a significant impairment of transitory otoacoustic emissions--a prospective multicenter cohort study.

BACKGROUND: Severe malaria may influence inner ear function, although this possibility has not been examined prospectively. In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria. An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions. Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above. METHODS: This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years. In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included. All malaria patients were treated with parental artesunate. RESULTS: In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening. In malaria patients, 58.5 % (n = 94, malaria vs controls p < 0.001, 95 % confidence interval 48.4-67.9 %) passed otoacoustic emission screening at the baseline measurement. The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria. The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria). Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis. This shows a significant impairment in the cerebral malaria group (p = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; p = 0.031 at day 14-28, 95 % confidence interval 24.5-66.3 %). CONCLUSION: The presented data show that 40 % of children have involvement of the inner ear early in severe malaria. In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

BACKGROUND: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. METHODS: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. RESULTS: Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. CONCLUSIONS: Blood-retina barrier breakdown occurs in three patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak from barrier dysfunction, and non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors

Cerebrospinal fluid Plasmodium falciparum histidine-rich protein-2 in pediatric cerebral malaria

Abstract Background Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM. Methods Patients included in the study were admitted (2009–2013) to the Pediatric Research Ward (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy. Enzyme-linked immunosorbent assay was used to determine plasma and CSF PfHRP-2 levels. Wilcoxon rank-sum tests and multivariable logistic regression analysis assessed the association of clinical and radiographic characteristics with the primary outcome of death during hospitalization. Results In this cohort of 94 patients, median age was 44 (interquartile range 29–62) months, 53 (56.4%) patients were male, 6 (7%) were HIV-infected, and 10 (11%) died during hospitalization. Elevated concentrations of plasma lactate (p = 0.005) and CSF PfHRP-2 (p = 0.04) were significantly associated with death. On multivariable analysis, higher PfHRP-2 in the CSF was associated with death (odds ratio 9.00, 95% confidence interval 1.44–56.42) while plasma PfHRP-2 was not (odds ratio 2.05, 95% confidence interval 0.45–9.35). Conclusions Elevation of CSF, but not plasma PfHRP-2, is associated with death in this paediatric CM cohort. PfHRP-2 egress into the CSF may represent alteration of blood brain barrier permeability related to the sequestration of parasitized erythrocytes in the cerebral microvasculature

Early Diagnosis, Treatment and Follow-Up of Cystic Echinococcosis in Remote Rural Areas in Patagonia: Impact of Ultrasound Training of Non-Specialists

Cystic echinococcosis (CE) is an important and widespread disease that affects sheep, cattle, and humans living in areas where sheep and cattle are raised. CE is highly endemic in rural sections of Rio Negro, Argentina, where our group is based. However, it requires continuous monitoring of both populations with human disease best assessed by means of ultrasound (US) screening. This is challenging in remote rural areas due to the shortage of imaging specialists. To overcome this hurdle, we set up a two-day training program of Focused Assessment with Sonography for Echinococcosis (FASE) on CE for family medicine practitioners with no previous experience in US. After the course, they were equipped with portable US scanners and dispatched to remote rural areas in Rio Negro where they screened patients, located and staged the cysts and decided on the treatment with the help of surgeons and radiologists in local tertiary care centers

Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond

Paediatric cerebral malaria is the most serious complication of Plasmodium falciparum infection. While the majority recover, long-term cognitive impairment has been highlighted as a significant and neglected problem. Persistent or serious deficits in processes such as attention or behavioural inhibition should be manifest in changes to performance on oculomotor tasks. Therefore we investigated the impact of cerebral malaria on the development of reflexive pro-saccades and antisaccades. In a longitudinal study, 47 children previously admitted with retinopathy-confirmed cerebral malaria (mean age at admission 54 months), were compared with 37 local healthy controls (mean ages at first study visit 117 and 110 months respectively). In each of three or four test sessions, over a period of up to 32 months, participants completed 100 prosaccade tasks and 100 antisaccade tasks. Eye movements were recorded using infrared reflectance oculography; prosaccade, correct antisaccade and error prosaccade latency, and antisaccade directional error rate were calculated. Hierarchical linear modelling was used to investigate the effect of age and the influence of cerebral malaria on these parameters. Data were also collected from an independent, older group (mean age 183 months) of 37 local healthy participants in a separate cross-sectional study. Longitudinal data exhibited the expected decrease in latency with age for all saccade types, and a decrease in the antisaccade directional error rate. Hierarchical linear modelling confirmed that age had a statistically significant effect on all parameters (p< = 0.001). However, there were no statistically significant differences between the cerebral malaria and control groups. Combining groups, comparison with the literature demonstrated that antisaccade directional error rate for the Malawi sample was significantly higher than expected, while latencies for all saccade types were indistinguishable from published. The high directional error rate was also confirmed in the older, healthy Malawian participants from the cross sectional study. Our observation of similar oculomotor performance in cerebral malaria and control groups at long follow-up periods suggests that cerebral malaria survivors are not at a generally increased risk of persistent cognitive deficits. Our data raise questions about the prevailing hypothesis that cerebral malaria has gross impacts on the development of processes such as attention and behavioural inhibition. More importantly, our novel finding of a clear difference in antisaccade performance between all of the Malawi participants and published data suggests that the Malawian paediatric population as a whole faces serious challenges to cognitive development beyond cerebral malaria

The Lung Image Database Consortium (LIDC): An Evaluation of Radiologist Variability in the Identification of Lung Nodules on CT Scans

RATIONALE AND OBJECTIVES: The purpose of this study was to analyze the variability of experienced thoracic radiologists in the identification of lung nodules on CT scans and thereby to investigate variability in the establishment of the “truth” against which nodule-based studies are measured. MATERIALS AND METHODS: Thirty CT scans were reviewed twice by four thoracic radiologists through a two-phase image annotation process. During the initial “blinded read” phase, radiologists independently marked lesions they identified as “nodule ≥ 3mm (diameter),” “nodule < 3mm,” or “non-nodule ≥ 3mm.” During the subsequent “unblinded read” phase, the blinded read results of all radiologists were revealed to each of the four radiologists, who then independently reviewed their marks along with the anonymous marks of their colleagues; a radiologist’s own marks then could be deleted, added, or left unchanged. This approach was developed to identify, as completely as possible, all nodules in a scan without requiring forced consensus. RESULTS: After the initial blinded read phase, a total of 71 lesions received “nodule ≥ 3mm” marks from at least one radiologist; however, all four radiologists assigned such marks to only 24 (33.8%) of these lesions. Following the unblinded reads, a total of 59 lesions were marked as “nodule ≥ 3 mm” by at least one radiologist. 27 (45.8%) of these lesions received such marks from all four radiologists, 3 (5.1%) were identified as such by three radiologists, 12 (20.3%) were identified by two radiologists, and 17 (28.8%) were identified by only a single radiologist. CONCLUSION: The two-phase image annotation process yields improved agreement among radiologists in the interpretation of nodules ≥ 3mm. Nevertheless, substantial variabilty remains across radiologists in the task of lung nodule identification