Estimating true hospital morbidity of complications associated with mumps outbreak, England, 2004/05

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1 Reserch rticle Estimting true hospitl morbidity of complictions ssocited with mumps outbrek, Englnd, 24/5 C Yung 1 2, M Rmsy ² 1. Infectious Disese Service, Deprtment of Peditrics, KK Women s nd Children s Hospitl, Singpore 2. Immunistion, Heptitis nd Blood Sfety Deprtment, Public Helth Englnd, London, United Kingdom Correspondence: Chee Fu Yung (cheefu.yung@gmil.com) Cittion style for this rticle: Yung C, Rmsy M. Estimting true hospitl morbidity of complictions ssocited with mumps outbrek, Englnd, 24/5. Euro Surveill. 216;21(33):pii=332. DOI: Article submitted on 21 July 215 / ccepted on 3 June 216 / published on 18 August 215 Mumps outbreks in highly vccinted popultions continue to be reported globlly. Therefore, quntifying the burden of mumps morbidity ccurtely will be necessry to better ssess the impct of mumps vccintion progrmmes. We im to estimte the true morbidity resulting from mumps complictions in terms of hospitlised orchitis, meningitis, oophoritis nd pncretitis in Englnd during the outbrek in 24/5. This outbrek in Englnd led to cler increse in hospitlistions coded to mumps for complictions of orchitis in those born in the 197s nd 198s nd possibly for meningitis in those born in the 198s. A simple sttisticl model, bsed on nlysing time trends for dignosed complictions in hospitl dtbses with routine lbortory surveillnce dt, found tht the ctul morbidity ws much higher. There were 2.5 times (166 cses) more mumps orchitis cses in the 197s cohort nd 2. times (78 cses) more mumps orchitis cses in the 198s cohort thn complictions coded to mumps in hospitl dtbses. Our study demonstrted tht the mumps outbrek in Englnd 24/5 resulted in substntil increse in hospitlised mumps complictions, nd the model we used cn improve the scertinment of morbidity from mumps outbrek. Introduction Mumps is n cute virl infection which cn present with fever, hedche nd swelling of the protid glnds (unilterl or bilterl). It cn be symptomtic in round 3% of children [1]. Reported complictions of mumps infection include orchitis, septic meningitis, oophoritis, pncretitis, encephlitis nd permnent unilterl defness [1-3]. The mesles, mumps, rubell (MMR) vccine ws introduced into the immunistion progrmme in the United Kingdom (UK) in October 1988 s single dose for children ged 12 to 15 months. In 1996, to provide dditionl protection ginst ll three infections, second dose ws dded to the schedule. In the first decde fter MMR vccine ws introduced, rtes of reported nd confirmed mumps infection fell to extremely low levels in the UK (42 confirmed mumps cses in 1998). Since 1998, however, there hve been number of mumps outbreks in dolescents culminting in ntionl epidemic in 24 nd 25, ffecting mny universities nd colleges cross Englnd nd Wles. The ge group minly ffected were those born before 1988, who hd not been offered routine childhood MMR vccintion nd who hd voided mumps exposure becuse of high coverge in younger children [4]. Although MMR coverge in two-yer-old children ws only c 8%, the outbrek dynmics did not result in significnt trnsmission in young children [5,6]. The introduction of second MMR dose for pre-schoolers in 1996 could be fctor which my hve contributed to this [4]. The number of lbortory-confirmed mumps cses rose from 5 in 22 to 1,541 in 23 to 8,129 in 24 nd 43,378 in 25 [5]. Routine dt on hospitlistions cn provide informtion on complictions of mumps if the dignosis of mumps is obvious nd coded correctly on dischrge. Delyed or missed dignoses hve been shown to occur, prticulrly in the bsence of history of protid swelling [7]. This my led to n underestimtion of complictions ttributble to mumps. As mumps outbreks in highly vccinted popultions continue to be reported globlly, quntifying the burden of mumps morbidity ccurtely will be necessry to better ssess the impct of mumps vccintion progrmmes [7-16]. In this pper, we used regression nlysis to ssess the contribution of lbortory-confirmed mumps cses to the hospitlistions for orchitis, meningitis, oophoritis nd pncretitis in ech birth cohort. Other common infections ssocited with meningitis were used s n dditionl prmeter in the regression model for meningitis only. This enbled us to estimte the number of hospitlised orchitis, meningitis, oophoritis nd 1

2 Figure 1 Four-weekly number of lbortory-confirmed mumps (n = 16,549) nd non-mumps (n = 93) virl meningitis infections, Englnd, April 22 Mrch Number of mumps cses with meningitis All non-mumps virl meningitis cses week verges (April 22 to Mrch 26) 7s(All Lb) 8s(serum) 8s(sliv) 9s(All Lb) All Non mumps virl meningitis Mumps infections strtified by birth cohort (nd lbortory smple type for 8s cohort only). pncretitis ttributble to the increse in mumps during the outbrek. Therefore, the im of the study ws to estimte the true morbidity resulting from mumps complictions in terms of hospitlised orchitis, meningitis, oophoritis nd pncretitis in Englnd during the mumps outbrek in 24/5. Methods Dt source Selection of birth cohort cses nd study period For the purpose of this study, dt were retrieved from 1 April 22 to 31 Mrch 26 from ll dt sources. As the mumps outbrek minly involved young dults, those born between 197 nd 1999 were included nd cses were divided into three birth cohort decdes for nlysis: 7s (197 79), 8s (198 89) nd 9s (199 99). These birth cohorts were ffected lrgely becuse they were not eligible for vccintion nd hd voided exposure during childhood. As the outbrek occurred over short time frme, the cohorts provide suitble proxy for ge while t the sme time keeping the modelling nlysis less complex. Lbortory-confirmed mumps cses Confirmed mumps infections re reported by lbortories in Englnd to Public Helth Englnd (PHE) (formerly the Helth Protection Agency). Clinicins who dignose mumps re lso required by sttute to notify the responsible public helth officer for the locl uthority, usully consultnt in Communicble Disese Control. Since 1995, ll notified cses of mumps hve been followed by n offer of orl fluid testing for IgM t PHE. The orl fluid test hd been shown to hve sensitivity of 9.3% nd specificity of 97.6% [17]. A high proportion of notified cses provided smples nd were tested using this method (5 8%) [18]. Some cses were confirmed on serum only using commercil mumps IgM ssys. Cses confirmed by testing for IgM in orl fluid or in serum were used to provide dt on trends in the 7s nd 9s cohort. In 25, during the pek of the outbrek, mumps orl fluid testing ws temporrily suspended in those born between 1981 nd Therefore, to void ny bis resulting from chnge in testing, only mumps confirmed by serum IgM 2

3 Figure 2 Regression model of hospitlised orchitis (A nd B) nd hospitlised meningitis cses (C), Englnd, April 22 Mrch 26 A. Hospitlised orchitis, 7s birth cohort (n = 4,623) Number of orchitis dmissions Dt Regression model week verges (April 22 to Mrch 26) Number of orchitis dmissions B. Hospitlised orchitis, 8s birth cohort (n = 5,559) Dt Regression model week verges (April 22 to Mrch 26) Number of meningitis dmissions C. Hospitlised meningitis cses, 8s birth cohort (n = 1,787) Dt Regression model week verges (April 22 to Mrch 26) 3

4 Tble 1 Hospitl dmissions of orchitis, meningitis, oophoritis nd pncretitis cses (n=27,133) nd cses coded s mumps (n=1,231), by birth cohort, Englnd, April 22 Mrch 26 Mumps compliction Birth cohort 7s 8s 9s Totl Orchitis Hospitl cses 4,623 5,559 2,265 12,447 Hospitl cses coded s mumps Meningitis Hospitl cses 1,978 1, ,59 Hospitl cses coded s mumps Oophoritis Hospitl cses ,673 Hospitl cses coded s mumps Pncretitis Hospitl cses 6,25 2, ,954 Hospitl cses coded s mumps testing ws used to derive trends for the 8s cohort in our model. In summry, cses were defined s individuls born between 197 nd 1999 with dignosis of lbortoryconfirmed mumps vi either IgM in orl fluid or serum from 1 April 22 to 31 Mrch 26. Hospitl dmissions dtbse Hospitl Episode Sttistics (HES) cpture ll dmissions (including dy dmissions) to Ntionl Helth Service (NHS) hospitls in Englnd. The dignoses recorded t the time of dischrge re coded using the Interntionl Clssifiction of Diseses-1 (ICD-1). A minimum dtset for ll dmissions with ny of the following codes ws extrcted: B26 (mumps), N45 (orchitis nd epididymitis), A87 (virl meningitis), N7 (oophoritis) nd K85 (cute pncretitis) [19]. The nonymised HESID field, which is unique ID generted from NHS Number, locl ptient identifier, postcode, sex nd dte of birth ws used to link episodes from the sme individul dmitted over the period [2]. Length of hospitl sty is clculted from dys between the dmission dte nd the dischrge dte. Non-mumps meningitis trend dt For the virl meningitis model only, to djust for the possible effect from non-mumps-relted cuses of meningitis, we included s n dditionl independent vrible trends of lbortory-confirmed infections with other viruses known to be commonly ssocited with meningitis. The trend informtion used for not mumps-relted cuses of meningitis ws derived from temporl dt on confirmed meningitis cses due to coxsckievirus A nd B, echovirus or untyped enterovirus during the study period. Becuse of the smll numbers involved, this ws included in ggregte form nd not broken down by birth cohort. Sttisticl nlysis We developed lest squre regression models which ssocited hospitl records of orchitis, meningitis, oophoritis nd pncretitis with prmeters of lbortory-confirmed mumps cses nd time. The formul for hospitl records of compliction Y in four-week period j ws: Formul 1 Yj = C + α Lj + γj where Y is the totl number of recorded complictions in the HES dtbse, j is unit time in intervls of four weeks, C is constnt representing bckground cses of compliction Y ttributble to non-mumps cuses, α is the coefficient for lbortory-confirmed mumps infection, L is the number of lbortory-confirmed mumps nd γ is the coefficient for unit of time (four weeks). We included γ to fctor in ge trends of mumps morbidity. Specificlly for meningitis, lbortoryconfirmed meningitis cses not due to mumps were included s n extr prmeter in the eqution. The vlues of α were estimted by lest squre regression in Microsoft Excel version 11. The finl model only included sttisticlly significnt explntory prmeters while non-significnt prmeters were dropped. The lest significnt prmeter ws removed first nd one t time. A prmeter ws only retined in the model if α remined significntly (p <.5) ssocited with hospitl record of compliction. The model ws lso eyeblled to ensure tht the fit to ctul dt ws resonble, tking into considertion the goodness-offit of the model s denoted by R2. The sttisticl models for ech birth cohort nd compliction generted vlue for the number of hospitl records of compliction ssocited with single lbortory-confirmed cse of mumps. This ws used to estimte the morbidity ttributble to the mumps outbrek in ech birth cohort nd compliction by the sum of α Lj during the study period from the eqution bove, which is denoted by: Formul 2 α Lj Complictions nd birth cohorts for which the ssocition with the prmeter lbortory-confirmed mumps ws not sttisticlly significnt (not p <.5) were dropped from the finl model. In such scenrio, the model estimted no complictions ttributble to the mumps outbrek. The method hs been used in similr wy to investigte hospitl dmissions due to rotvirus, the 4

5 Tble 2 Orchitis nd meningitis morbidity in hospitlised mumps cses ttributble to mumps outbrek, by birth cohort, Englnd, 24/5 (n =1,798) Orchitis Meningitis Birth cohort 7s 8s 9s 7s 8s 9s Intercept (C) Coefficient for mumps cse (α) Coefficient for unit time (γ).14 (.8.21).32 (.1.54).23 (.2.27).5(.18.92).58 (.44.73) Coefficient for non-mumps meningitis NA NA NA.64 (.47.81).5 (.25.75).31 (.4.59) R Estimted cses ttributble to mumps ( α L j ) NA: not pplicble. Prmeter dropped from model s not significnt. 279 ( ) 1,519 (1,366 1,87) contribution of respirtory syncytil virus to bronchiolitis nd pneumoni-ssocited hospitlistion nd to evlute the contribution of serogroup C meningococcl infections to cliniclly dignosed cses of meningitis nd septicemi [21-23]. Results Lbortory-confirmed infections The timing of the mumps outbrek in 24/5 ws pprent in lbortory-confirmed mumps cses in ll three birth cohorts, prticulrly those born in the 8s cohort (Figure 1). Cses confirmed by orl fluid (sliv) in the ltter cohort declined slightly erlier thn in the other birth cohorts becuse of the restriction on orl fluid testing in this ge group. Trends over time in the cses confirmed by serum testing in the 8s cohort, however, were similr to overll trends in the other cohorts. There were 9 lbortory-confirmed infections due to coxsckievirus A nd B, echovirus nd untyped enterovirus between April 22 nd Mrch 26. The trend in non-mumps cuses of meningitis fluctuted over time, decresing during the mumps outbrek period. Mumps-coded hospitl dmissions for orchitis, meningitis, oophoritis or pncretitis (HES dtbse) Between April 22 nd Mrch 26, there were totl of 2,284 hospitlistions with dignostic code for mumps mong those born between 197 nd Of these, 95 (42%), 143 (6%), 138 (6%) nd (%) lso hd second dignosis code for orchitis, meningitis, pncretitis nd oophoritis, respectively. For hospitlised mumps orchitis, the 8s cohort contributed the lrgest numbers with 811 cses, while the 9s cohort ws lest represented with only 26 cses. The verge length of sty for hospitlised mumps ws shortest in the 9s cohort with 1.3 dys, compred with 2.2 dys nd 1.9 dys in the 7s nd 8s cohorts, respectively. The pttern of highest burden in the 8s cohort nd lowest burden in the 9s cohort ws similr for mumps meningitis nd pncretitis but t smller scle due to the smller number of such complictions (Tble 1). Non-mumps-coded hospitl dmissions for orchitis, meningitis, oophoritis nd pncretitis (HES dtbse) Between April 22 nd Mrch 26, there were totl of 12,447 hospitl dmissions for orchitis, 4,59 hospitl dmissions for meningitis, 1,673 hospitl dmissions for oophoritis nd 8,954 hospitl dmissions for pncretitis in ptients born between 197 nd 1999 (Tble 1). The number of hospitl dmissions for orchitis in the 7s nd 8s birth cohorts peked in 24/5 coinciding with the pek of the mumps outbrek (Figure 2). Looking t the rw dt, there lso ppered to be slight increse in hospitlistions for meningitis cses t this time in people born in the 8s (Figure 2C). However, the model did not demonstrte ny sttisticlly significnt increse over the period. None of the other hospitl records of orchitis, meningitis, oophoritis nd pncretitis by birth cohort showed ny obvious spikes coinciding with the increse in lbortory confirmed mumps cses. Modelling to estimte true morbidity ssocited with mumps outbrek The regression model ws produced for hospitlistion with orchitis, meningitis, oophoritis nd pncretitis for the three birth cohorts (7s, 8s nd 9s). Only the models for orchitis in the 7s nd 8s cohort were sttisticlly significnt for ll prmeters. The models found 2.5 times more mumps orchitis in the 7s cohort (166 cses) nd 1.9 times more mumps orchitis in the 8s cohort (78 cses) when compred with the number of cses in ech cohort tht were coded s mumps in hospitl dtbses (HES). Aprt from the 5

6 two outcomes bove, ll other outcomes hd no excess morbidity ttributble to the mumps outbrek ccording to the model generted (Tble 2). Discussion The 24/5 mumps outbrek in Englnd led to n increse in hospitlistions coded s mumps orchitis in those born in the 197s nd 198s nd possibly those coded s mumps meningitis in those born in the 198s. Our regression models echo these findings but found tht the true burden of hospitlised mumps orchitis ws times greter thn the number of cses ctully coded s mumps in hospitl dtbses. There ws no obvious increse in other complictions or ge cohorts coinciding with the outbrek but there ws suggestion of higher numbers of mumps-coded pncretitis (114 cses) in hospitl records in those born in the 198s. During the yers of low mumps incidence following introduction of the MMR vccine, mumps morbidity due to orchitis, meningitis, pncretitis nd oophoritis ws rre. The resurgence of mumps despite high coverge with two-dose MMR in mny countries my require improved monitoring of mumps complictions s well s my require considertion of new strtegies. Mumps orchitis ws the most common reson for hospitlistion, ccounting for 42% of ll hospitlised mumps cses, similr to lrge outbreks reported from the Netherlnds nd from Jewish communities in the United Sttes nd Isrel [7,15,24]. The high numbers of mumps orchitis in current mumps outbreks my be ttributed to the high ttck rtes in dolescents nd young dults. Although mumps orchitis hs been shown to cuse cute zoospermi nd oligospermi, the potentil of mumps orchitis to led to infertility in post-pubertl mles remins uncler [25-29]. Our model demonstrted the limittion of using hospitl surveillnce records lone to study dmissions ttributble to mumps. To improve the qulity of the dt, clinicins would need to ctively seek history of mumps in ptients who present with orchitis, meningitis nd pncretitis, nd to record the history of recent mumps in the dischrge summry. Better recording, however, is unlikely to fully resolve the issue of underscertinment of mumps complictions s mny ptients my not hve been wre tht they hve hd mumps. Bsed on our model, the true burden of mumps orchitis would be 2 or 2.5 fold higher compred with cses ctully coded s mumps in hospitl dtbses during mumps epidemic. However, even this level is likely to be minimum since we hve only looked t hospitlised morbidity. Nevertheless, our findings should provide quntifiction to better estimte the true burden of hospitlised mumps morbidity. This hs importnt implictions for improving vccintion uptke t the frontline s well s describing the overll impct of mumps vccintion s the progrmme evolves. Anlysis of the hospitlised mumps popultion showed tht the number of mumps complictions vried between birth cohorts. Overll, those born in the 199s hd fewer complictions nd shorter men hospitl sty (by n verge of.75 dys) compred with the other birth cohorts. Regression modelling identified similr pttern with higher morbidity from orchitis in those born in the 197s nd 198s compred with the 199s birth cohort. It is unlikely tht this is simply due to difference in the number of mumps cses during the outbrek. Lbortory surveillnce dt suggest tht the number of confirmed cses ws similr in the 197s nd 199s cohorts. A possible explntion is the protective effect of MMR vccintion ginst complictions. Previously, we found tht MMR vccintion reduces the risk of hospitlistion, orchitis nd meningitis despite vccine filure [3]. A similr protective effect of MMR vccine especilly ginst mumps orchitis hve lso been found in United Sttes, the Netherlnds nd Isrel [15,24,31]. In Englnd, the 9s cohort, unlike the other cohorts, were likely to hve received t lest one or more doses of MMR s MMR vccine ws only introduced into the ntionl progrmme in October The model ws unble to detect n increse in hospitl morbidity for meningitis, oophoritis or pncretitis in the ffected cohorts. This is consistent with the observed lck of oophoritis coded s mumps but t odds with the increse in pncretitis with mumps code (138 cses) in routine hospitl dtbses. Moreover, the sttisticl model ws not ble to detect spike in hospitlised meningitis in the 8s cohort coinciding with the mumps outbrek. This highlights the limittion of the model nd suggests tht the burden of morbidity from the mumps outbrek is likely to be minimum estimte. Other limittions included the ssumption tht ll the prmeters ccounting for the reported vrition in four-weekly numbers of hospitlistions were included in the model. In ddition, we could only investigte complictions tht resulted in cute hospitl dmissions nd we could not investigte long-term sequele such s defness resulting from mumps. Conclusion Our study showed tht the mumps outbrek in Englnd 24/5 resulted in substntil increse in mumps complictions of orchitis, pncretitis nd possibly meningitis with subsequent hospitlistions. We hve shown tht nlysing time trends for ll dignoses of complictions in hospitl dtbses with routine lbortory surveillnce dt in simple sttisticl model cn improve the scertinment of morbidity from mumps outbrek. This method incresed the morbidity due to mumps-relted orchitis hospitlistions by fctor of 2 or 2.5 when compred with those coded s mumps lone. 6

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