Effective use of data linkage is becoming an increasingly important focus in the new healthcare system in England. We linked data from the results of a multiplex PCR assay for respiratory viruses for a population of 230 inpatients at a UK teaching hospital with their patient administrative system records in order to compare the mortality and length of stay of patients who tested positive for influenza A(H1N1)pdm09 with those positive for another influenza A virus. The results indicated a reduced risk of death among influenza A(H1N1)pdm09 patients compared to other influenza A strains, with an adjusted risk ratio of 0·25 (95% confidence interval 0·08-0·75, P = 0·01), while no significant differences were found between the lengths of stay in the hospital for these two groups. Further development of such methods to link hospital data in a routine fashion could provide a rapid means of gaining epidemiological insights into emerging infectious diseases

Curran, MD

Reacher, M

Roddick, I

Smith, C

UCL Discovery

SHORT REPORTUse of linked electronic health records to assessmortality and length of stay associated with pandemicinﬂuenza A(H1N1)pdm09 at a UK teaching hospitalC. SMITH1,2*, M. D. CURRAN3, I. RODDICK1 AND M. REACHER11Field Epidemiology Services –Cambridge, Public Health England, Cambridge, UK2Department of Infection and Population Health, Centre for Infectious Disease Epidemiology, University CollegeLondon, London, UK3Clinical Microbiology and Public Health Laboratory, Public Health England, Addenbrooke’s Hospital,Cambridge, UKReceived 10 February 2014; Final revision 17 July 2014; Accepted 23 July 2014;ﬁrst published online 14 August 2014SUMMARYEffective use of data linkage is becoming an increasingly important focus in the new healthcaresystem in England. We linked data from the results of a multiplex PCR assay for respiratoryviruses for a population of 230 inpatients at a UK teaching hospital with their patientadministrative system records in order to compare the mortality and length of stay of patientswho tested positive for inﬂuenza A(H1N1)pdm09 with those positive for another inﬂuenza Avirus. The results indicated a reduced risk of death among inﬂuenza A(H1N1)pdm09 patientscompared to other inﬂuenza A strains, with an adjusted risk ratio of 0·25 (95% conﬁdenceinterval 0·08–0·75, P = 0·01), while no signiﬁcant differences were found between the lengths ofstay in the hospital for these two groups. Further development of such methods to link hospitaldata in a routine fashion could provide a rapid means of gaining epidemiological insights intoemerging infectious diseases.Key words: Infectious disease epidemiology, inﬂuenza A.Linkage of electronic health records to connect infor-mation across disparate sources can represent a valu-able tool for medical and population health research[1]. The importance of exploiting such tools hasbeen highlighted numerous times during the develop-ment of the new healthcare system in England:Public Health England included improved data shar-ing as one of its key priorities for strengthening publichealth surveillance [2], and NHS England and theHealth and Social Care Information Centre are aim-ing to link data for patients across health and socialcare systems through the development of the care.data service [3]. However, the process of linking data-sets that have not been designed with this objective inmind can be complex, as there is not always a con-sistent unique identiﬁer that can be used to match arecord from one database to a corresponding recordfor the same patient (or encounter, depending on thepurpose), in another database. Data structures oftendiffer, requiring multiple entries to be matched to asingle row in another database, and completeness ofkey linking ﬁelds is not always prioritized in dataentry.When the pandemic inﬂuenza A(H1N1)pdm09virus emerged in 2009, uncertainty regarding its nat-ure and severity prompted efforts to rapidly determinethe burden of mortality and morbidity associated with* Author for correspondence: Miss C. Smith, Department ofInfection and Population Health, Centre for Infectious DiseaseEpidemiology, University College London, London, UK.(Email: catherine.smith.13@ucl.ac.uk)Epidemiol. Infect. (2015), 143, 1125–1128. © Cambridge University Press 2014doi:10.1017/S0950268814002076This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/3.0/), whichpermits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.the strain [4]. In this study, we aimed to demonstratehow linkage of routinely collected hospital datacould be used to address this question and similarand population-level concerns.This was a retrospective study of a group of inpati-ents at a UK teaching hospital who tested positive foran inﬂuenza A virus by multiplex PCR betweenNovember 2007 and December 2012. Laboratorymultiplex PCR results were linked to their results ina second genotyping database to determine viral sub-types. Corresponding records were also identiﬁed inthe Patient Administration System (PAS), allowingidentiﬁcation of inpatients, the reason for theiradmission, discharge destination, and admission anddischarge dates. Microsoft SQL Server 2005(Microsoft Corp., USA) was used to perform the link-age, based on patients’ hospital numbers, names andhospital spell identiﬁcation numbers (an identiﬁer forthe continuous stay of a patient in a hospital).Deaths were identiﬁed using the discharge destinationﬁeld, and length of stay following a positive inﬂuenzaA test was calculated using the testing and dischargedates.The multiplex PCR assay for respiratory virusesused at this hospital includes a pentaplex inﬂuenzaA/B/A(H1N1)pdm09/H3 detection and typing real-time assay with an internal control, which has beendetailed previously [5, 6], with additional multiplexreal-time (Taqman) PCR assays to detect othercommon respiratory viruses including respiratory syn-cytial viruses (RSV) A and B, parainﬂuenza types 1–4,adenovirus, enterovirus, rhinovirus, human meta-pneumovirus, group 1 coronaviruses (HCoV-229Eand HCoV-NL63), group 2 coronaviruses, andSARS-associated coronavirus [7].Distributions of mortality and length of stay follow-ing a positive inﬂuenza A test were compared for(H1N1)pdm09 and other inﬂuenza A cases, and rela-tionships assessed using univariable and multivariablelog-binomial regression analyses as appropriate.The study population comprised 243 patients whotested positive for inﬂuenza A, from a total of 4895inpatients who had a multiplex respiratory PCR testduring their admission between November 2007 andDecember 2012. Successful linkages between the mul-tiplex PCR, genotype, and PAS databases wereobtained for all records with the exception of 13patients who tested positive for inﬂuenza A but forwhom no genotyping results were available and weretherefore excluded from the analysis. Linkages wereachieved based on the combination of hospitalnumbers and hospital spell identiﬁers and checkedmanually using names. A total of 160 (70%) of the230 included patients had inﬂuenza A(H1N1)pdm09,with the remaining 70 testing positive for anotherinﬂuenza A strain, including 62 H3 and eight non-pandemic H1 isolates which typed as the seasonalH1N1 strain circulating prior to and during theearly phase of the pandemic in 2009.Five inﬂuenza seasons were included in the data.The pandemic H1N1(pdm09) strain ﬁrst arose in the2008/2009 season, and predominated for the nexttwo seasons, until 2011/2012 in which no H1N1cases were detected.About half (118, 51%) of the patients were maleand the median age was 34·5 years [inter-quartilerange (IQR) 10–67·5 years]. The majority of thepatients (182, 79%) were admitted for a respiratoryreason, and 32 (14%) tested positive for at least oneother respiratory virus. Of these, ﬁve had oneco-infection, 26 had two co-infections and one hadthree co-infections; the most common co-infectingviruses were rhinovirus and RSV (11 and 10 patients,respectively).A total of 13 patients in the population died whilein hospital. These fatalities included four (2·5%) ofthe 160 patients with H1N1 inﬂuenza A, and nine(13%) of the 70 patients with non-H1N1 inﬂuenzaA. The results of the univariable and multivariablelog-binomial regression analyses for the outcome ofdeath are shown in Table 1. The crude risk ratio(RR) for death following an infection with inﬂuenzaA(H1N1)pdm09 compared to other inﬂuenza Aviruses was 0·19 [95% conﬁdence interval (CI) 0·06–0·61, P< 0·01]. A larger proportion of patients aged565 years died, with a RR of 16·5 (95% CI 2·17–126·2, P< 0·01) compared to the baseline group(those aged 0–16 years). There were non-signiﬁcantassociations between male sex and reduced risk ofdeath (RR 0·42, 95% CI 0·13–1·33, P = 0·13), and be-tween presence of a co-infection and increased risk ofdeath (RR 1·13, 95% CI 0·26–4·84, P = 0·88). None ofthe 48 patients who were admitted for a non-respiratory reason died.Multivariable analysis was performed adjusting forage, as a signiﬁcant covariate, and sex, as an a prioriconfounder, but not co-infection or reason for ad-mission as they were not signiﬁcantly associated withdeath at univariable analysis. The adjusted RR forinﬂuenza A(H1N1)pdm09 increased to 0·25 (95% CI0·08–0·75, P = 0·01), which suggests that the crudeRR was partially confounded by these factors.1126 C. Smith and othersThe median lengths of stay in the hospital followinga positive test for inﬂuenza A among patients withinﬂuenza A(H1N1)pdm09 and other inﬂuenza Aviruses were 3 days (IQR 1–9 days) and 4 days (IQR2–12 days), respectively. Inspection of the distribu-tions did not suggest any differences between thesegroups, and a Wilcoxon–Mann–Whitney testconﬁrmed that the distributions were not signiﬁcantlydifferent (P = 0·32).This study was the ﬁrst analysis of linked multiplexrespiratory virus PCR and patient administration sys-tem data from this hospital. The successful linkage ofthese datasets allowed the detailed virological infor-mation that had been collected over ﬁve inﬂuenza sea-sons to be enriched with demographic and clinicaldata in order to address this important epidemiologi-cal problem.The results provided evidence that inﬂuenza A(H1N1)pdm09 was less severe in terms of mortalitythan other inﬂuenza A viruses, with a risk of deathabout one quarter that of seasonal inﬂuenza A. Nosigniﬁcant differences were found in the lengths ofstay in the hospital for these two groups. These resultsare consistent with other reports that the pandemicstrain was less severe than initially anticipated [8],and did not result in as many deaths as other inﬂuenzapandemics in the 20th century [9, 10].The case-fatality ratio (CFR) in this population forpandemic inﬂuenza A(H1N1)pdm09 was 2·5%. Sincethis study concerned hospitalized patients only, it isnot surprising that this value exceeds some otherreported values, such as the estimated CFR in theUK from the ﬁrst year of the pandemic of 0·04% [11],which was calculated using estimated number of clinicalcases from surveillance data as the denominator andnumber of deaths associated with inﬂuenza A(H1N1)pdm09 as the numerator. A recent review [12] identiﬁeda wide range of published CFRs from this pandemic,with higher estimates from hospitalized cases, and atenfold increase in the CFR for those requiring inten-sive care compared to all symptomatic cases.There were a number of limitations to this studywhich impact on its generalizability to other inﬂuenzaA patient populations. First, although the reason foradmission could be classiﬁed as respiratory or non-respiratory, there was not enough clinical informationavailable to generate an accurate measure of underly-ing conditions in the patients, which therefore couldnot be controlled for in the analysis. Previous studieshave indicated that factors such as pregnancy, immu-nosuppression and neurological disorders [13], arerelated to severe infection and would therefore be im-portant to consider. Bacterial co-infections have alsobeen associated with fatal cases of inﬂuenza A(H1N1)pdm09 infection [14], a ﬁnding that could beassessed through linkage with other routinely col-lected hospital laboratory data, although full reviewsof clinical notes would be required to provide acomplete understanding of the pre-existing medicalconditions.Table 1. Univariable and multivariable analyses for effect of inﬂuenza A strain type on risk of death among inpatientstesting positive for inﬂuenza A at a UK teaching hospital, November 2007 to December 2012Total DiedUnivariable analysis Multivariable analysisVariable Level (N = 230) (N = 13) % RR 95% CI P aRR 95% CI PInﬂuenza AvirusNon-H1N1* 70 9 12·85 Base — — — — —(H1N1)pdm09 160 4 2·50 0·19 0·06–0·61 <0·01 0·25 0·08–0·75 0·01Age, years 0–16 62 1 1·61 Base — — — — —17–64 138 4 2·90 1·80 0·21–15·75 0·60 2·34 0·27–20·60 0·44565 30 8 26·67 16·5 2·17–126·22 <0·01 14·09 1·83–108·43 0·01Sex Female 112 9 8·04 Base — — — — —Male 118 4 3·39 0·42 0·13–1·33 0·13 0·58 0·21–1·60 0·29Co-infection† No 198 11 5·56 Base — — — — —Yes 32 2 6·25 1·13 0·26–4·84 0·88 — — —Reason foradmissionRespiratory 182 13 7·14 — — — — — —Non-Respiratory 48 0 0 — — — — — —RR, Risk ratio; CI, conﬁdence interval; aRR, adjusted risk ratio (multivariable log-binomial regression of effect of inﬂuenzaA strain type on risk of death, adjusted for age and sex)* Non-H1N1, any inﬂuenza A virus except (H1N1)2009† Co-infection, positive test for any other respiratory virus by multiplex PCRLinkage of records for inﬂuenza A(H1N1)pdm09 1127Second, the mortality outcome was calculatedusing only the patient discharge destination, andtherefore captured only patients who died while inhospital. Linkage to death registers would enable bet-ter understanding of the possible effects of these virusstrains on mortality, but this was beyond the scope ofthis study.Third, the data collected were limited to inpatientsat one teaching hospital across ﬁve inﬂuenza seasons.The study population is therefore not representativeof the entire population of patients with inﬂuenzaA across these seasons, as inpatients at this hospitalare likely to have more severe disease than non-inpatients, and may have complicated pre-existingconditions.Finally, there was a potential admission bias inthis study: during the pandemic, public awareness ofinﬂuenza was heightened, and, although public healthadvice recommended that symptomatic individualsstay at home [15], it is possible that there were relaxedadmission standards during the ﬁrst phase of thepandemic. More liberal admission criteria couldhave led to an increase in the number of non-severecases admitted compared to other inﬂuenza seasonsand therefore contributed to the observed associationwith reduced mortality. However, no formal policy tothis effect was introduced at this hospital, and such asituation would also be likely to lead to a reduction inthe average length of stay, which was not detectedhere.In spite of these limitations, the association betweeninﬂuenza A(H1N1)pdm09 H1N1 and reduced mor-tality among inﬂuenza A patients was strong, andprovides further evidence that this strain of inﬂuenzawas not as severe as was ﬁrst feared. Moreover, thisanalysis emphasizes the value of combining databasesof electronic healthcare records to make the best useof routinely collected data. Further development ofsuch data linkage methods in a routine fashioncould provide a rapid means of gaining valuableepidemiological insights into emerging infectiousdiseases.ACKNOWLEDGEMENTSWe acknowledge the laboratory staff at theClinical Microbiology and Public Health Laboratorywho performed the routine molecular respiratorytests.DECLARATION OF INTERESTNone.REFERENCES1. Karmel R, Rosman D. Linkage of health and aged careservice events: comparing linkage and event selectionmethods. BMC Health Services Research 2008; 8: 149.2. DH PHE Transition Team. Public health surveillance –towards a strategy for Public Health England. London, 2012.3. NHS England. Care episode statistics: technical speciﬁ-cation of the GP extract. Leeds, 2013.4. Garske T, et al. Assessing the severity of the novelinﬂuenza A/H1N1 pandemic. British Medical Journal2009; 339: b2840.5. Ellis JS, Curran MD. Simultaneous molecular detectionand conﬁrmation of inﬂuenza AH5, with internalcontrol. Methods in Molecular Biology (Clifton, NJ)2011; 665: 161–181.6. Wu LT, et al. Duplex molecular assay intended forpoint-of-care diagnosis of inﬂuenza A/B virus infection.Journal of Clinical Microbiology 2013; 51: 3031–3038.7. Tanner HE, et al. Viral respiratory infections during the2009 inﬂuenza A(H1N1) outbreak in the West MidlandsRegion, UK. Epidemiology and Infection 2012; 140:1551–1556.8. Presanis AM, et al. The severity of pandemic H1N1inﬂuenza in the United States, from April to July2009: a Bayesian analysis. PLoS Medicine 2009; 6:e1000207.9. Khandaker G, et al. Systematic review of clinical andepidemiological features of the pandemic inﬂuenza A(H1N1) 2009. Inﬂuenza and Other Respiratory Viruses2011; 5: 148–156.10. Donaldson LJ, et al. Mortality from pandemic A/H1N12009 inﬂuenza in England: public health surveillancestudy. British Medical Journal 2009; 339: b5213–b5213.11. Pebody RG, et al. Pandemic Inﬂuenza A (H1N1) 2009and mortality in the United Kingdom: risk factors fordeath, April 2009 to March 2010. Eurosurveillance2010; 15(20).12. Punpanich W, Chotpitayasunondh T. A review on theclinical spectrum and natural history of humaninﬂuenza. International Journal of Infectious Diseases2012; 16: e714–723.13. Writing Committee of the WHO Consultation onClinical Aspects of Pandemic (H1N1) 2009 Inﬂuenza.Clinical aspects of pandemic 2009 inﬂuenza A (H1N1)virus infection. New England Journal of Medicine2010; 362: 1708–1719.14. Shieh WJ, et al. 2009 pandemic inﬂuenza A (H1N1):pathology and pathogenesis of 100 fatal cases in theUnited States. American Journal of Pathology 2010;177: 166–175.15. Hine D. The 2009 inﬂuenza pandemic: an independentreview of the UK response to 2009 inﬂuenza pandemic.London: Department of Health, 2010.1128 C. Smith and others

Use of linked electronic health records to assess mortality and length of stay associated with pandemic influenza A(H1N1)pdm09 at a UK teaching hospital

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Use of linked electronic health records to assess mortality and length of stay associated with pandemic influenza A(H1N1)pdm09 at a UK teaching hospital

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