Would a good screening test increase the effectiveness of border screening for influenza control?
Authors: L.A. Selvey, R. Hall
Journal: Clinical Microbiology and Infection (2017)

The international spread of communicable diseases has been recognized as a public health problem for hundreds of years. Attempts have been made, with varying degrees of success, to prevent communicable diseases from crossing international borders back to the fifteenth century. During the 1918/19 influenza pandemic, efforts were made to prevent influenza from spreading internationally, including strict maritime quarantine in Australia. In spite of these efforts influenza spread worldwide, and reached Australia, then a very geographically isolated country, in early 1919 [[1]Curson P. McCracken K. An Australian perspective of the 1918–1919 influenza pandemic.NSW Public Health Bull. 2006; 17: 103-107Crossref PubMed Google Scholar]. Annual seasonal influenza epidemics, usually involving two to four influenza strains, occur worldwide because of regular antigenic drift and, occasionally, major antigenic shifts result in influenza pandemics [[2]Biggerstaff M. Cauchemez S. Reed C. Gambhir M. Finelli L. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature.BMC Infect Dis. 2014; 14: 480Crossref PubMed Scopus (293) Google Scholar]. These antigenic changes mean that acquired immunity through infection or vaccination does not convey protection over time, making influenza difficult to control. Although the influenza reproduction number is generally estimated as being low (R0 ∼ 2–3), the serial interval between successive generations of influenza cases is short (∼2 days) [[2]Biggerstaff M. Cauchemez S. Reed C. Gambhir M. Finelli L. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature.BMC Infect Dis. 2014; 14: 480Crossref PubMed Scopus (293) Google Scholar], so that even small numbers of introduced cases can rapidly result in a large outbreak in a susceptible population. Because influenza is so difficult to prevent, there is continuing interest in preventing the importation of influenza to unaffected communities, particularly when an influenza strain of pandemic potential evolves, or when a seasonal influenza strain causes more severe disease. This involves border screening and identification and quarantining of infected individuals until they are no longer infectious. Chen et al. [[3]Chen J. Yang K. Zhang M. Shen C. Chen J. Wang G. et al.Rapid identification of imported influenza viruses at Xiamen International Airport via an active surveillance program.Clin Microbiol Infect. 2018; 24: 289-294Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] describe the implementation of a rapid influenza screening test to detect incoming passengers infected with seasonal influenza at Xiamen International Airport in China. Without a rapid diagnostic test, large numbers of symptomatic individuals infected with viruses other than influenza would need to be quarantined until the results of a laboratory test are available. Hence, identification of cases needs a test that is logistically easy to apply, is of high sensitivity and reasonable specificity, and is economically justifiable in order to make this approach practically feasible. Chen et al. point out that previously described rapid influenza tests have a low sensitivity [[3]Chen J. Yang K. Zhang M. Shen C. Chen J. Wang G. et al.Rapid identification of imported influenza viruses at Xiamen International Airport via an active surveillance program.Clin Microbiol Infect. 2018; 24: 289-294Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Meta-analyses have found that sensitivity of rapid tests varies between tests, between children and adults, and between viral strains [4Chartrand C. Leeflang M.M. Minion J. Brewer T. Pai M. Accuracy of rapid influenza diagnostic tests: a meta-analysis.Ann Intern Med. 2012; 156: 500-511Crossref PubMed Scopus (345) Google Scholar, 5Merckx J. Wali R. Schiller I. Caya C. Gore G.C. Chartrand C. et al.Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction: a systematic review and meta-analysis.Ann Intern Med. 2017; 167: 394-409Crossref PubMed Scopus (167) Google Scholar]. Chen et al. found a high sensitivity for the ‘Flu Dot’ rapid ELISA test used on incoming passengers who have an ‘influenza-like illness’ when compared with virus culture [[3]Chen J. Yang K. Zhang M. Shen C. Chen J. Wang G. et al.Rapid identification of imported influenza viruses at Xiamen International Airport via an active surveillance program.Clin Microbiol Infect. 2018; 24: 289-294Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. However, this is only part of the problem in screening for influenza among arriving passengers, and the issue of sensitivity needs to be considered on the basis of the entire screening pathway. This depends on the sensitivity of the presence of both influenza-like illness and positive findings on the rapid ELISA test in the identification of cases. Influenza virus-infected individuals who are not identified as having influenza-like illness will not be tested and therefore will not be detected at the border. In one study, Priest et al. estimated the sensitivity of self-reported symptoms of an influenza-like illness with or without measured temperature for the detection of seasonal influenza in a random sample of travellers arriving in New Zealand during the southern hemisphere influenza season. They found a sensitivity of 11.5% (95% CI 5.6–17.3) for the detection of influenza cases using self-reported symptoms of an influenza-like illness and a sensitivity of 2.5% (95% CI 0.4–4.6) for symptoms of an influenza-like illness together with fever detected with a thermometer [[6]Priest P.C. Jennings L.C. Duncan A.R. Brunton C.R. Baker M.G. Effectiveness of border screening for detecting influenza in arriving airline travelers.Am J Public Health. 2013; 103: 1412-1418Crossref PubMed Scopus (19) Google Scholar]. Combining this with Chen et al.’s estimate of sensitivity of the ‘Flu Dot’ rapid ELISA test (96.7%) gives an overall sensitivity of 11.1% for screening for symptoms of influenza-like illness combined with the ‘Flu Dot’ rapid ELISA test. Although the sensitivity of symptoms of influenza-like illness will vary according to the influenza virus strain [[6]Priest P.C. Jennings L.C. Duncan A.R. Brunton C.R. Baker M.G. Effectiveness of border screening for detecting influenza in arriving airline travelers.Am J Public Health. 2013; 103: 1412-1418Crossref PubMed Scopus (19) Google Scholar], it is unlikely to approach 100%. In a cohort study from December 2007 to June 2010, Wang et al. identified asymptomatic seasonal H1N1 and pandemic H1N1(2009) influenza cases. They found no differences in the peak viral load between asymptomatic and symptomatic cases [[7]Wang B. Russell M.L. Fonseca K. Earn D.J.D. Horsman G. Van Caeseele P. et al.Predictors of influenza a molecular viral shedding in Hutterite communities.Influenza Other Respir Virus. 2017; 11: 254-262Crossref PubMed Scopus (14) Google Scholar]. This also points to the lack of sensitivity of symptom-based screening for influenza-like illness at the border, and that transmission of influenza is possible from an asymptomatic case. The effectiveness of screening arriving travellers needs to be assessed against objectives and costs incurred and/or avoided. Objectives may be defined in terms of the size, shape and timing of the influenza epidemic wave; or by the consequent morbidity and mortality. It may be useful to delay the wave, reduce its amplitude and reduce the rate of infection, even if the total number of cases is unchanged or even increased. Alternatively, we can focus on subsequent mortality and morbidity, with less emphasis on the number of cases per se. If we define the objective of border control as making a significant contribution to the reduction in influenza morbidity and mortality, success will depend on the effectiveness of all components in the border control pathway, including the ability to successfully intervene having identified a proportion of incoming cases [[8]Selvey L.A. Antão C. Hall R. Entry screening for infectious diseases in humans.Emerg Infect Dis. 2015; 21: 197-201Crossref PubMed Scopus (36) Google Scholar]. Modelling studies suggest that international travel restrictions of even 90% success would only delay the spread of pandemics for 3–4 weeks and have a minimal impact on the size of the pandemic [[9]Mateus A.L. Otete H.E. Beck C.R. Dolan G.P. Nguyen-Van-Tam J.S. Effectiveness of travel restrictions in the rapid containment of human influenza: a systematic review.Bull World Health Organ. 2014; 92 (868–880D)Crossref PubMed Scopus (74) Google Scholar]. A systematic review of the experience of countries implementing border screening and quarantine strategies to control importations of influenza during the 2009 pandemic showed that outbreaks of untraceable origin were delayed by only 7–12 days with the lower confidence interval being zero [[10]Cowling B.J. Lau L.L. Wu P. Wong H.W. Fang V.J. Riley S. et al.Entry screening to delay local transmission of 2009 pandemic influenza A (H1N1).BMC Infect Dis. 2010; 10: 82Crossref PubMed Scopus (91) Google Scholar]. Chen et al. demonstrate high sensitivity of the ELISA test compared with viral culture in passengers who have declared an influenza-like illness. However, travellers who are infectious with influenza may not suffer from, or declare, such an illness. Experience in the field with pandemic influenza in 2009 showed that cases were frequently diagnosed after entry to the country; this was documented in several countries, for example, Singapore, Japan and Australia [[8]Selvey L.A. Antão C. Hall R. Entry screening for infectious diseases in humans.Emerg Infect Dis. 2015; 21: 197-201Crossref PubMed Scopus (36) Google Scholar]. This imposes a requirement for not only high sensitivity of screening, but also rapid implementation of a screening regimen. In addition, feasibility and cost-effectiveness need to be considered. Airport arrival screening is labour-intensive, and during an influenza epidemic health staff may not be available for airport screening duties. Screening and management of arrivals is expensive, particularly the costs of staff time. It may be that there are more economically efficient means of influenza control within the community. Current technology limits our ability to control the transmission of influenza. However, because influenza is associated with substantial morbidity and mortality public health control of influenza is a worthwhile objective. Unfortunately it would seem that border entry screening and quarantine play a limited role in influenza control. The authors have no conflicts of interest to declare. This study was funded by the Australian Government Department of Health and Ageing. Linda Selvey and Robert Hall contributed equally to the writing of this manuscript.