Cost-effectiveness of incorporating Ebola prediction score tools and rapid diagnostic tests into a screening algorithm: A decision analytic model.

BACKGROUND: No distinctive clinical signs of Ebola virus disease (EVD) have prompted the development of rapid screening tools or called for a new approach to screening suspected Ebola cases. New screening approaches require evidence of clinical benefit and economic efficiency. As of now, no evidence or defined algorithm exists. OBJECTIVE: To evaluate, from a healthcare perspective, the efficiency of incorporating Ebola prediction scores and rapid diagnostic tests into the EVD screening algorithm during an outbreak. METHODS: We collected data on rapid diagnostic tests (RDTs) and prediction scores' accuracy measurements, e.g., sensitivity and specificity, and the cost of case management and RDT screening in EVD suspect cases. The overall cost of healthcare services (PPE, procedure time, and standard-of-care (SOC) costs) per suspected patient and diagnostic confirmation of EVD were calculated. We also collected the EVD prevalence among suspects from the literature. We created an analytical decision model to assess the efficiency of eight screening strategies: 1) Screening suspect cases with the WHO case definition for Ebola suspects, 2) Screening suspect cases with the ECPS at -3 points of cut-off, 3) Screening suspect cases with the ECPS as a joint test, 4) Screening suspect cases with the ECPS as a conditional test, 5) Screening suspect cases with the WHO case definition, then QuickNavi™-Ebola RDT, 6) Screening suspect cases with the ECPS at -3 points of cut-off and QuickNavi™-Ebola RDT, 7) Screening suspect cases with the ECPS as a conditional test and QuickNavi™-Ebola RDT, and 8) Screening suspect cases with the ECPS as a joint test and QuickNavi™-Ebola RDT. We performed a cost-effectiveness analysis to identify an algorithm that minimizes the cost per patient correctly classified. We performed a one-way and probabilistic sensitivity analysis to test the robustness of our findings. RESULTS: Our analysis found dual ECPS as a conditional test with the QuickNavi™-Ebola RDT algorithm to be the most cost-effective screening algorithm for EVD, with an effectiveness of 0.86. The cost-effectiveness ratio was 106.7 USD per patient correctly classified. The following algorithms, the ECPS as a conditional test with an effectiveness of 0.80 and an efficiency of 111.5 USD per patient correctly classified and the ECPS as a joint test with the QuickNavi™-Ebola RDT algorithm with an effectiveness of 0.81 and a cost-effectiveness ratio of 131.5 USD per patient correctly classified. These findings were sensitive to variations in the prevalence of EVD in suspected population and the sensitivity of the QuickNavi™-Ebola RDT. CONCLUSIONS: Findings from this study showed that prediction scores and RDT could improve Ebola screening. The use of the ECPS as a conditional test algorithm and the dual ECPS as a conditional test and then the QuickNavi™-Ebola RDT algorithm are the best screening choices because they are more efficient and lower the number of confirmation tests and overall care costs during an EBOV epidemic.

Development of Ebola virus disease prediction scores: Screening tools for Ebola suspects at the triage-point during an outbreak.

BACKGROUND: The control of Ebola virus disease (EVD) outbreaks relies on rapid diagnosis and prompt action, a daunting task in limited-resource contexts. This study develops prediction scores that can help healthcare workers improve their decision-making at the triage-point of EVD suspect-cases during EVD outbreaks. METHODS: We computed accuracy measurements of EVD predictors to assess their diagnosing ability compared with the reference standard GeneXpert® results, during the eastern DRC EVD outbreak. We developed predictive scores using the Spiegelhalter-Knill-Jones approach and constructed a clinical prediction score (CPS) and an extended clinical prediction score (ECPS). We plotted the receiver operating characteristic curves (ROCs), estimated the area under the ROC (AUROC) to assess the performance of scores, and computed net benefits (NB) to assess the clinical utility (decision-making ability) of the scores at a given cut-off. We performed decision curve analysis (DCA) to compare, at a range of threshold probabilities, prediction scores' decision-making ability and to quantify the number of unnecessary isolation. RESULTS: The analysis was done on data from 10432 subjects, including 651 EVD cases. The EVD prevalence was 6.2% in the whole dataset, 14.8% in the subgroup of suspects who fitted the WHO Ebola case definition, and 3.2% for the set of suspects who did not fit this case definition. The WHO clinical definition yielded 61.6% sensitivity and 76.4% specificity. Fatigue, difficulty in swallowing, red eyes, gingival bleeding, hematemesis, confusion, hemoptysis, and a history of contact with an EVD case were predictors of EVD. The AUROC for ECPS was 0.88 (95%CI: 0.86-0.89), significantly greater than this for CPS, 0.71 (95%CI: 0.69-0.73) (p < 0.0001). At -1 point of score, the CPS yielded a sensitivity of 85.4% and specificity of 42.3%, and the ECPS yielded sensitivity of 78.8% and specificity of 81.4%. The diagnostic performance of the scores varied in the three disease contexts (the whole, fitting or not fitting the WHO case definition data sets). At 10% of threshold probability, e.g. in disease-adverse context, ECPS gave an NB of 0.033 and a net reduction of unnecessary isolation of 67.1%. Using ECPS as a joint approach to isolate EVD suspects reduces the number of unnecessary isolations by 65.7%. CONCLUSION: The scores developed in our study showed a good performance as EVD case predictors since their use improved the net benefit, i.e., their clinical utility. These rapid and low-cost tools can help in decision-making to isolate EVD-suspicious cases at the triage point during an outbreak. However, these tools still require external validation and cost-effectiveness evaluation before being used on a large scale.

Baseline characterization of epilepsy in an onchocerciasis endemic area of the Democratic Republic of Congo.

Increased epilepsy prevalence is reported in onchocerciasis (OC) endemic areas and is associated with the occurrence of distinct syndromes such as nodding disease and Nakalanga syndrome. To date, a causal relationship between OC and epilepsy is still a matter of controversy. We conducted a case-control study of participants with epilepsy and age- and gender-matched presumably healthy controls to elucidate the relationships between OC and epilepsy and explore the role of inflammation and growth factors in an OC endemic area in the Democratic Republic of Congo (DRC). Eighty-two participants with epilepsy (mean age ± SD: 23.2 ± 8.7 years) and 27 controls (mean age ± SD: 22.3 ± 12.0 years) underwent snip skin biopsies to determine Onchocerca volvulus infection status. Serum concentrations of cytokines, chemokines, and growth factors were measured using a Luminex Multiplex Assay kit. Children <19 years of age underwent neurocognitive assessments using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II). Overall, epilepsy was associated with OC (OR = 4.51, z = 3.11, p = 0.0019), and children with OC were more likely to be severely stunted (OR = 11.67, z = 2.62, p = 0.0087). The relationship between epilepsy and OC was no longer significant (z = 1.27, p = 0.20) when stunting was included as a correcting covariate. Epilepsy was associated with poor KABC-II test scores, high serum levels of IL-17, and low levels of IL-1RA, IL-8, and EGF. KABC-II testing scores correlated with serum levels of IL-10, MCP-1 and HGF. Familial history of epilepsy occurred frequently. Future studies should consider cytokines and/or growth factors when assessing susceptibility to epilepsy in OC endemic areas. Additional investigations, preferentially in low-prevalence OC areas, may provide further insights into the concept, risk, and burden of river epilepsy.

Cyanide and the human brain: perspectives from a model of food (cassava) poisoning.

Threats by fundamentalist leaders to use chemical weapons have resulted in renewed interest in cyanide toxicity. Relevant insights may be gained from studies on cyanide mass intoxication in populations relying on cyanogenic cassava as the main source of food. In these populations, sublethal concentrations (up to 80 µmol/l) of cyanide in the blood are commonplace and lead to signs of acute toxicity. Long-term toxicity signs include a distinct and irreversible spastic paralysis, known as konzo, and cognition deficits, mainly in sequential processing (visual-spatial analysis) domains. Toxic culprits include cyanide (mitochondrial toxicant), thiocyanate (AMPA-receptor chaotropic cyanide metabolite), cyanate (protein-carbamoylating cyanide metabolite), and 2-iminothiazolidine-4-carboxylic acid (seizure inducer). Factors of susceptibility include younger age, female gender, protein-deficient diet, and, possibly, the gut functional metagenome. The existence of uniquely exposed and neurologically affected populations offers invaluable research opportunities to develop a comprehensive understanding of cyanide toxicity and test or validate point-of-care diagnostic tools and treatment options to be included in preparedness kits in response to cyanide-related threats.

On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure.

Konzo is a self-limiting central motor-system disease associated with food dependency on cassava and low dietary intake of sulfur amino acids (SAA). Under conditions of SAA-deficiency, ingested cassava cyanogens yield metabolites that include thiocyanate and cyanate, a protein-carbamoylating agent. We studied the physical and biochemical modifications of rat serum and spinal cord proteins arising from intoxication of young adult rats with 50-200mg/kg linamarin, or 200mg/kg sodium cyanate (NaOCN), or vehicle (saline) and fed either a normal amino acid- or SAA-deficient diet for up to 2 weeks. Animals under SAA-deficient diet and treatment with linamarin or NaOCN developed hind limb tremors or motor weakness, respectively. LC/MS-MS analysis revealed differential albumin carbamoylation in animals treated with NaOCN, vs. linamarin/SAA-deficient diet, or vehicle. 2D-DIGE and MALDI-TOF/MS-MS analysis of the spinal cord proteome showed differential expression of proteins involved in oxidative mechanisms (e.g. peroxiredoxin 6), endocytic vesicular trafficking (e.g. dynamin 1), protein folding (e.g. protein disulfide isomerase), and maintenance of the cytoskeleton integrity (e.g. α-spectrin). Studies are needed to elucidate the role of the aformentioned modifications in the pathogenesis of cassava-associated motor-system disease.

Monocyclic and dicyclic hydrocarbons: structural requirements for proximal giant axonopathy.

The chromogenic and neurotoxic gamma-diketone 1,2-diacetylbenzene (1,2-DAB), but not its isomer 1,3-DAB, induces blue discoloration of tissues and urine, clustering of axonal microtubules and proximal neurofilament-filled axonal swellings in rodents. The remarkable chromogenic property of 1,2-DAB, a monocyclic aromatic hydrocarbon, arises from reaction with lysine residues of proteins and formation of dimeric and polymeric derivatives. Tetralin, a dicyclic solvent structurally related to acetyl ethyl tetramethyl tetralin, a chromogenic and neurotoxic agent, reportedly induces excretion of green urine, and causes neurological disturbances in humans. Monocyclic aromatic 1,2,4-triethylbenzene (1,2,4-TEB), but not its isomer 1,3,5-TEB, is also reportedly chromogenic and induces neurophysiological deficits in rodents consistent with axonal neuropathy, but without neuropathological confirmation. We treated 12-week-old C57Bl/6 mice by gavage with 300, 600, or 900 mg/kg/day 1,2,4-TEB, or equivalent doses of 1,3,5-TEB, 3 days/week, for up to 12 weeks, or intraperitoneally with 400 mg/kg/day tetralin, or 50 or 100 mg/kg/day of its alpha-tetralol analogue, 5 days/week, for up to 5 weeks. Animals treated with 1,2,4-TEB, but not 1,3,5-TEB, tetralin or alpha-tetralol, developed hind limb weakness, excreted greenish urine, and showed 1,2-DAB-like neuropathology. These findings support the hypothesis that 1,2-spaced ethyl (or acetyl) moieties on a benzene ring of hydrocarbons are required for hydrocarbons to induce chromogenic changes and proximal giant neurofilamentous axonopathy. Key molecular targets of these compounds likely reside in the axon where they serve to maintain normal cytoskeletal organization.