Rapid diagnostics for Ebola in emergency settings
2015; Elsevier BV; Volume: 386; Issue: 9996 Linguagem: Inglês
10.1016/s0140-6736(15)61119-9
ISSN1474-547X
Autores Tópico(s)Global Security and Public Health
ResumoRapid case finding and diagnosis have been cornerstones of the strategy to stem the 2014–15 Ebola epidemic.1Blackley DJ Lindblade KA Kateh F et al.Rapid intervention to reduce Ebola transmission in a remote village—Gbarpolu county, Liberia, 2014.MMWR Morb Mortal Wkly Rep. 2015; 64: 175-178PubMed Google Scholar However, during most of this epidemic, timely laboratory confirmation of Ebola virus disease has been complicated by the delay between recognition of a patient with suspected Ebola virus disease in the community, transport or self-presentation of this patient to a treatment site for phlebotomy, and the time needed to transport the sample to a laboratory equipped to run molecular diagnostics safely.2WHO Ebola Response TeamEbola virus disease in West Africa—the first 9 months of the epidemic and forward projections.N Engl J Med. 2014; 371: 1481-1495Crossref PubMed Scopus (1149) Google Scholar This delay has had devastating effects not only at the population level, by extending opportunities for transmission, but also for individual patients.3Dhillon RS Srikrishna D Garry RF Chowell G Ebola control: rapid diagnostic testing.Lancet Infect Dis. 2015; 15: 147-148Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar More than 50% of patients in a suspected disease ward of an Ebola treatment facility can eventually be given an alternate diagnosis.4O'Shea MK Clay KA Craig DG et al.Diagnosis of febrile illnesses other than Ebola virus disease at an Ebola treatment unit in Sierra Leone.Clin Infect Dis. 2015; (published online May 19.)https://doi.org/10.1093/cid/civ399Crossref Scopus (35) Google Scholar Accurate rapid diagnostic tests, particularly those that can be completed at the point of care, could move the timing and place of diagnosis closer to the community in which a patient with suspected Ebola virus disease is first seen, halting transmission chains and allowing better allocation of scarce health-care resources. Field deployment of rapid diagnostic tests in geographically isolated areas could also identify individuals positive for Ebola in their community who choose home care with provision of the appropriate physical resources and infection control support, preventing a potentially arduous journey for treatment that might reduce chances of survival.3Dhillon RS Srikrishna D Garry RF Chowell G Ebola control: rapid diagnostic testing.Lancet Infect Dis. 2015; 15: 147-148Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 5Perkins MD Kessel M What Ebola tells us about outbreak diagnostic readiness.Nat Biotechnol. 2015; 33: 464-469Crossref PubMed Scopus (30) Google Scholar Additionally, the phlebotomy generally required for real-time reverse transcription PCR (RT-PCR) testing adds additional staff safety risks.6Strecker T Palyi B Ellerbrok H et al.Field evaluation of capillary blood samples as a collection specimen for the rapid diagnosis of Ebola virus infection during an outbreak emergency.Clin Infect Dis. 2015; (published online May 19.)https://doi.org/10.1093/cid/civ397Crossref PubMed Scopus (25) Google Scholar Point-of-care rapid diagnostic tests that can be done with a reduced volume of capillary blood can not only reduce the risk of percutaneous injury, but might also be more amenable for use in patients who are dehydrated. In The Lancet, Jana Broadhurst and colleagues7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar present data from a field validation study comparing the performance of the ReEBOV Antigen Rapid Test kit, which detects the VP40 matrix protein of Ebola virus, against a benchmark RT-PCR assay, done in a field reference laboratory. Blood samples were taken from 106 patients with suspected Ebola who presented to two treatment facilities in Sierra Leone between Feb 3, and Feb 20, 2015. ReEBOV was assessed against the altona test (used plasma) as a true point-of-care modality with fingerstick samples, and at the reference laboratory using whole blood (collected by venepuncture) samples. The rapid diagnostic test had impressive results, detecting all cases that were positive by altona RT-PCR in both point-of-care (28 [26·7%] of 105 samples; sensitivity 100% [95% CI 87·7–100]) and reference laboratory testing (45 [16·2%] of 277 samples; sensitivity 100% [92·1–100]). A small subset of samples that were RT-PCR-negative were deemed positive by the rapid diagnostic test (six of 77 in the point-of-care test and 18 of 232 in the reference laboratory samples), yielding specificity of 92·2% (95% CI 83·8–97·1 and 88·0–95·3, respectively). Discordant samples were retested with a second RT-PCR assay (Trombley), showing a greater concordance between the Trombley assay and ReEBOV than between altona and ReEBOV; however, three of 18 samples concordant on rapid diagnostic test and altona were also positive by the Trombley assay, all with a cycle threshold greater than 33·5. Herein lies the difficulty. As the authors note,7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar how can the performance of the rapid diagnostic test be interpreted if the benchmark method itself (altona) might not be reliable, particularly at high cycle threshold values (associated with low levels of viraemia)? Additionally, the distribution of cycle threshold values in this study were only up to 26·3 (with a positive test being cycle threshold <40), and hence the data do not provide good information on how the rapid diagnostic test will perform very early on in the disease course, or towards convalescence. The rapid diagnostic test was read by two independent operators, and all nine disagreements between the readers occurred with a positivity score of 1+, correlating with higher cycle threshold values on altona PCR. This finding suggests that practical use of the rapid diagnostic test will need careful confirmation for patients early or late in their disease course even in the cycle threshold value range reported in this cohort.7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar Finally, the rapid diagnostic test assay needs refrigeration for storage, which the authors suggest might be available in most secondary health centres in the endemic area, but could restrict field deployment to more geographically isolated areas in which most Ebola outbreaks start and where the need is greatest.8Fauci AS Ebola—underscoring the global disparities in health care resources.N Engl J Med. 2014; 371: 1084-1086Crossref PubMed Scopus (134) Google Scholar Broadhurst and colleagues' Article7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar is the only reported study for the ReEBOV test, which has been approved by WHO for emergency use.9WHOFirst antigen rapid test for Ebola through emergency assessment and eligible for procurement.http://www.who.int/medicines/ebola-treatment/1st_antigen_RT_Ebola/en/Date: 2015Google Scholar The sheer logistical, staff safety, and administrative obstacles that exist for research in Ebola treatment facilities make the successful completion of this study7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar a feat in itself. Additionally, a dearth of data is available regarding how this and other rapid Ebola diagnostics perform in the field. In view of the drop in reported cases of Ebola since January, 2015, as the outbreak has come under control, the opportunity to do further bedside testing has decreased. With such emergent issues at stake, all data need to be accounted for, leaving researchers with the dilemma of how to interpret the available information cautiously and glean what is possible to support clinical guidelines and public health policies, while further information regarding the validity of the assay in a larger cohort is gathered. The study by Broadhurst and colleagues7Broadhurst MJ Kelly JD Miller A et al.ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study.Lancet. 2015; (published online June 26.)http://dx.doi.org/10.1016/S0140-6736(15)61042-XPubMed Google Scholar makes three important contributions. First, it validates the accuracy of the ReEBOV rapid diagnostic test in patients with advanced illness who are expected to have low cycle threshold values. This result suggests that the test could be used to triage this subset of patients if RT-PCR is not available, particularly in those with a high index of clinical suspicion for a differential diagnosis. Second, the data presented provide crucial information about the point-of-care function of this rapid diagnostic test, such as ease of use, quality of samples taken at the bedside, and the concordance with venous samples. Lastly, the results raise caution regarding the performance of the widely used altona RT-PCR assay, which the authors suggest might have underperformed because of laboratory-specific technical and performance factors, such as choice of RNA extractions and amplification methods. The performance of altona RT-PCR needs to be reexamined in other laboratories operating during this epidemic; the performance limitations of the altona assay were also shown in another study from Guinea.10Janvier F Gorbatch S Queval L et al.Difficulties of interpretation of Zaire Ebola Virus PCR results and implication in the field.J Clin Virol. 2015; 67: 36-37Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar False negatives by altona RT-PCR were of patients with Ebola who were potentially falsely ruled out and returned to their community while still infectious. Considering that more than 27 000 cases of Ebola have been reported in the present epidemic in west Africa, existing data for new treatments and diagnostic modalities are quite sparse.5Perkins MD Kessel M What Ebola tells us about outbreak diagnostic readiness.Nat Biotechnol. 2015; 33: 464-469Crossref PubMed Scopus (30) Google Scholar, 11WHOEbola situation report: June 3, 2015.http://apps.who.int/ebola/ebola-situation-reportsDate: 2015Google Scholar Aside from capacity building for humanitarian response, the Ebola epidemic has shown the importance of support for research infrastructure in endemic countries.12Heymann DL Chen L Takemi K et al.Global health security: the wider lessons from the west African Ebola virus disease epidemic.Lancet. 2015; 385: 1884-1901Summary Full Text Full Text PDF PubMed Scopus (293) Google Scholar In the interim, the largest challenges will be in interpretation of existing data and integration of these into the continued response. I was a technical adviser for Partners in Health's clinical Ebola response programme in Sierra Leone. I declare no competing interests. ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation studyThe ReEBOV rapid diagnostic test had 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing in this population (maximum cycle threshold 26·3). With two independent readers, the test detected all patients who were positive for Ebola virus by altona real-time RT-PCR; however, this benchmark itself had imperfect sensitivity. Full-Text PDF
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