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Journal of Clinical Virology 48 2010 104 108 Contents lists available at ScienceDirect Journal of Clinical Virology journal homepage Burden of disease due to human coronavirus and periodicity of infection Lia van der Hoek a Gabriele Ihorst b Klaus Sure c Astrid Michel de Vries a Johannes Forster e Ben Berkhout a Klaus a Infection Academic b c d e article Article history Received 18 December 2009 Received in revised form 17 February 2010 Accepted 27 February 2010 Keywords Human Croup Burden Background The disease burden caused by recently identified respiratory viruses like HCoV NL63 is unknown Objectives We determined the burden of disease due to HCoV NL63 infections using the population based PRI DE cohort of children under the age of 3 with lower respiratory tract infections LRTIs 1 respiratory the and tified HCoV NL63 CI virus 1386 6532 doi coronavirus NL63 of disease Study design In total 1756 respiratory samples from hospitalized children or children who visited the outpatient clinic were tested for HCoV NL63 Sampling covered a period of 2 years and the frequency of infection in different years was compared to other Western European studies that tested for this virus in 2 or more consecutive years Results Sixty nine samples were HCoV NL63 positive 35 were with high loads and of these 25 were single HCoV NL63 infections Based on the number of children with high HCoV NL63 infection and no additional infection the overall annual incidence in outpatients was 7 per 1000 children per year 95 confidence interval CI 3 13 per 1000 children per year which can be extrapolated to an absolute num ber of 16 929 visits to the physician due to an HCoV NL63 infection in Germany per year The estimated hospitalization rate is 22 per 100 000 children 95 CI 7 49 per 100 000 children per year This number reflects 522 HCoV NL63 children in Germany per year A large year to year difference in HCoV NL63 infection frequency was observed Combining these data with those of other studies in Western Europe revealed that HCoV NL63 infections follow a 2 year inter epidemic period with peaks of infection in the winters of 2000 2001 2002 2003 and 2004 2005 p 0 0001 Conclusions HCoV NL63 infection in children below 3 years of age often requires a visit to the physician in an outpatient clinic especially during peak years but hospitalizations are relatively infrequent 2010 Elsevier B V All rights reserved Background Coronavirus infections of humans are mostly restricted to the tract The human coronaviruses were first identified in mid 1960s HCoV 229E and HCoV OC43 1 3 but in 2003 2004 2005 three new human coronavirus species have been iden SARS CoV HCoV NL63 and HCoV HKU1 respectively 4 7 was first described in a child with bronchiolitis in Ams Abbreviations LRTI lowerrespiratorytractinfection HCoV humancoronavirus confidence intervals NPS nasopharyngeal secretions RSV respiratory syncytial PIV human parainfluenza virus Corresponding author Tel 31 20 5667510 fax 31 20 6916531 E mail address c m vanderhoek amc uva nl L van der Hoek terdam the Netherlands 6 but it soon turned out that HCoV NL63 infection occurs frequently in children 8 10 is observed around the globe reviewed in Ref 11 and infection is associated with croup and acute otitis media 10 12 2 Objectives The disease burden caused by respiratory viruses is huge in chil dren which led to the development of vaccines that can be used in young children For the new respiratory viruses the disease burden is unknown therefore we determined the burden of disease due to HCoV NL63infectionsinthepopulation basedstudy PRI DEstudy on children under the age of 3 with lower respiratory tract infec tions LRTI The PRI DE study covers 2 years and children were see front matter 2010 Elsevier B V All rights reserved 10 1016 j jcv 2010 02 023 Laboratory of Experimental Virology Department of Medical Microbiology Center for Medical Center of the University of Amsterdam Meibergdreef 15 1105 AZ Amsterdam Center for Clinical Trials and Institute of Medical Biometry and Medical Informatics University Department of Molecular and Medical Virology Ruhr University Bochum Germany Laboratory of Virology University Hospital of Caen Caen France Department of Pediatrics St Josefs Hospital Freiburg Germany info abstract NL63 infections Vabret d Ronald Dijkman a Uberla c and Immunity Amsterdam CINIMA The Netherlands Hospital Freiburg Germany L van der Hoek et al Journal of Clinical Virology 48 2010 104 108 105 recruited in the north east south and west of Germany at pedi atric practices and referral children s hospitals 13 This study design ascertained representation of the German children as 95 of them have a pediatrician and in case of hospitalization over 95 of them are referred to a children s hospital 3 Study design 3 1 Participants materials and laboratory testing Paediatric practices outpatients and hospitals inpatients from Hamburg Bochum Freiburg and Dresden participated in the study 13 Children with clinical signs of apnoea under the age of 6 months laryngotracheitis croup bronchitis bronchiolitis or pneumonia were included in the study Signs and symptoms were defined according to Denny and Clyde 14 Recruitment covered the period from November 1999 to October 2001 Nasopharyn geal secretions NPS were collected in a standardized manner as described 13 Of the 3 677 NPS that were collected within the PRI DE study half were randomly assigned to this study The randomiza tion was performed via a program generating random numbers in order to distribute samples equally between 2 different laborato ries The ethics committee of each participating center approved the study protocol and written informed consent was obtained from parents of all children RNA was extracted and tested for RSV PIV 1 PIV 2 PIV 3 influenza viruses and HCoV NL63 by hexaplex PCR and real time RT PCR as described 10 Samples collected in France winter 2003 2004 and the Netherlands 2002 till 2005 that were screened for HCoV NL63 were analyzed as described 6 15 Furthermore data from literature were included only for those studies that screened consecutive years in Western Europe and in which each year the sample selection criteria did not change Thus a year to year difference is a reflection of periodicity of infection 3 2 Incidence calculations i e 100 infection rates obtained from our analysis The PRI DE population at risk was determined using numbers of well baby visits which are attended regularly 16 These figures were used to estimate total numbers of LRTI cases and HCoV NL63 LRTI cases in the German pediatric population based on German census data population size on December 31st 1999 data from Statistisches Bundesamt Statistisches Jahrbuch 2001 3 3 Hospitalization rates Figures for the total number of hospitalizations in the German pediatric population were determined by applying the observed proportion of HCoV NL63 related LRTI cases in the PRI DE study hospitals to the total number of hospitalizations in 1999 in Ger many data from Statistisches Bundesamt Statistisches Jahrbuch 2002 interpolation of age groups 0 1 year and 1 5 years 3 4 Confidence intervals 95 confidence intervals CIs for incidence rates and hospital ization rates were obtained by calculating exact 97 5 CIs from the binomial distribution for infection rates and combining these with 97 5 CIs for the hospitalization rate due to LRTI or annual LRTI incidence rate 16 4 Results 4 1 Burden of disease The PRI DE study is a prospective population based study One can thus calculate the annual incidence rate and the total national disease burden attributable to HCoV NL63 related LRTIs in chil dren under the age of 3 years This calculation uses national census data outpatients and national hospital statistics inpatients In total 1756 PRI DE samples are included in the present study repre HCoV NL63 tested 657 490 208 401 936 535 284 1015 734 134 423 965 398 545 194 Incidence rates were estimated based on the PRI DE results 13 an incidence of lower respiratory tract infections of 28 7 per children per year seen by a doctor and using HCoV NL63 Table 1 Comparison of demographic clinical and virological characteristics of PRI DE HCoV NL63 study Category PRI DE study patients Study region Freiburg 1350 Dresden 995 Bochum 467 Hamburg 865 Age 0 year 1989 1 year 1115 2 years 569 M F Male 2133 Female 1533 Diagnosis Croup 290 Bronchitis 851 Bronchiolitis or wheezing bronchitis 2054 Pneumonia 853 Apnoea 80 Virus detected RSV A B 1247 PIV 1 2 3 377 INF A B 141 p 0 000 two sided Fisher s exact test senting 48 of the total number of samples that were collected To confirm whether the HCoV NL63 tested samples were representa tive for the entire PRI DE study which comprised 3677 children we checked collection dates study region age male female distri study population and the randomly selected subgroup of the present patients HCoV NL63 positive patients 49 24 3 6 49 24 4 9 44 6 2 9 46 15 3 7 47 31 3 3 48 25 4 7 50 13 4 6 48 43 4 2 48 26 3 5 46 18 13 4 50 18 4 3 47 31 3 2 47 8 2 0 37 46 0 0 0 43 28 5 1 51 6 3 1 63 45 0 0 0 106 L van der Hoek et al Journal of Clinical Virology 48 2010 104 108 Table 2 HCoV NL63 analysis on PRI DE samples Month of sampling PRI DE samples collected HCoV NL63 study patients of PRI DE study Nr of samples positive for HCoV NL63 November 1999 162 69 43 1 1 4 December 1999 213 90 42 1 1 1 January 2000 307 130 42 3 2 3 February 2000 292 139 47 3 2 2 March 2000 347 156 45 0 0 April 2000 151 73 48 2 2 7 May 2000 83 41 49 June 2000 36 15 42 July 2000 28 13 46 August 2000 44 20 45 September 2000 82 40 49 October 2000 103 51 50 November 2000 215 108 50 December 2000 279 134 48 January 2001 344 171 49 February 2001 227 114 50 March 2001 205 107 52 April 2001 148 75 51 May 2001 95 41 43 June 2001 65 31 48 July 2001 45 24 53 August 2001 22 11 50 September 2001 73 35 48 October 2001 111 68 61 bution diagnosis virus detection and determined that in none of these categories there was any bias in sample selection shown in Tables clinic 38 and Similar croup HCoV NL63 of the responding The sponding during nation infections frequently association 1 and 2 Of the 1756 children 685 visited the outpatient and 1071 were hospitalized In total we detected 69 HCoV NL63 infections 3 9 Of these were children visiting the outpatient clinic 5 5 of outpatients 31childrenwerehospitalized 2 9 ofallhospitalizedpatients to what was published previously 10 a high frequency of was noted in the HCoV NL63 infected children 26 1 of all positives p 0 0001 two sided Fisher s exact test The peak of infection was centered around the winter months each year Fig 1 When we include all HCoV NL63 infections n 69 to calculate the burden of disease a total of 16 visits to physician per 1000 children per year were calculated cor to 37 841 visits to a physician per year in Germany hospitalization rate is 85 per 100 000 children per year corre to 2022 hospitalizations per year in Germany However double infections it is debatable whether one or the combi of the two viruses causes the disease encountered Double with HCoV NL63 and a second respiratory virus were found 49 3 Furthermore we observed a very strong between a high HCoV NL63 viral load and single infec Fig 1 Percentage HCoV NL63 positive samples in the PRI DE study 0 0 0 0 0 0 0 0 0 0 0 0 9 8 3 18 13 4 12 7 0 13 11 4 4 3 7 0 0 1 2 4 0 0 0 0 0 0 1 2 9 1 1 5 tions and in case of double infections the viral load was low p 0 0001 Wilcoxon s two sample test 10 To ascertain that the disease burden is calculated for HCoV NL63 infections only and not influenced by infections with another respiratory virus we included only those infections which were not accompanied by a second respiratory virus n 35 Furthermore we included merely HCoV NL63 infections with high viral load which was arbitrarily defined as samples with more than 10 000 copies per ml n 25 Using these restrictions we calculated that the annual incidence of HCoV NL63 infection was 7 per 1000 children per year 95 confidence interval CI 3 13 per 1000 children per year reflecting an absolute number of 16 929 visits to the physician in Germany per year 95 CI 7255 31 440 The estimated hospitalization rate due to HCoV NL63 alone is 22 per 100 000 children 95 CI 7 49 per 100 000 children per year This number reflects 522 children in Germany per year 95 CI 166 1163 which is a conservative estimate 4 2 Periodicity of infection The winter season is the preferred season for infection by HCoV NL63 yet large year to year differences in frequency is apparent As shown in Fig 1 infection by HCoV NL63 is limited to a small percentage in the first year of the study whereas in the winter of 2000 01 the frequency reaches levels above 10 This indi 17 cates that there is an inter epidemic period but it cannot be determined whether HCoV NL63 peaks every 2 3 or more years To investigate this periodicity and the inter epidemic period we combined literature data and performed additional screening for HCoV NL63 in hospitalized patients and outpatients with acute respiratory infections in the Netherlands and France during the period 2001 till 2005 A higher frequency of infection in the win ters of 2000 01 2002 03 and 2004 05 and less infections in the 2001 02 and 2003 04 winter was observed Table 3 and 15 18 19 indicating that the frequency is high every other year To verify whether the inter epidemic period is 2 years we combined all our data and the published data on HCoV NL63 screenings during 2 or more consecutive years in Western Europe 6 19 23 and confirmed that in 2000 2001 2002 2003 and 2004 2005 significantly higher infection rates are observed compared to 1999 2000 2001 2002 and 2003 2004 combined rates 4 5 vs 1 5 p 0 0001 Chi square test Fig 2 L van der Hoek et al Journal of Clinical Virology 48 2010 104 108 107 Table 3 Overview of HCoV NL63 screening in Western European studies covering 2 or more consecutive years Country Years tested a Samples tested Samples positive Percentage positive Reference The Netherlands 2001 85 4 4 71 19 2002 54 0 0 00 19 2003 578 9 1 56 6 this study 2004 40 0 0 00 6 this study 2005 258 6 2 33 6 this study 22 1999 Fig studies higher test 1999 2000 p noticeable rates 5 are Therefore tunity population Most tion at tigate and Belgium 2003 233 2004 70 Switzerland 2000 22 2001 28 2002 10 2003 16 2004 22 2005 22 2006 2 Germany 2000 726 2001 916 2002 114 Sweden 2004 116 2005 106 France 2003 300 2004 200 2005 1002 a A year is defined from August to July e g year 2000 is the period between August 2 Percentage HCoV NL63 positive samples in Western Europe the included are described in Table 3 A year is defined from August to July significantly percentage compared to years 99 00 01 02 and 03 04 p 0 0001 Chi square We found no significant differences when comparing 2001 2002 and 2003 2004 rates 1 5 1 1 1 6 0 92 Chi square test with 2df but modest differences were when comparing 2000 2001 2002 2003 and 2004 2005 6 4 3 8 3 8 p 0 003 Chi square test with 2df Discussion In Germany paediatricians are available for all children and they consulted instead of general practitioners for primary care sampling in paediatric practices provides the oppor to collect a representative patient set that reflects the of German children that are ill but not hospitalized studies that have looked at the frequency of HCoV NL63 infec in patients with respiratory infections have focused exclusively hospitalized patients In the PRI DE study it is possible to inves the frequency of infection in both groups those hospitalized those visiting the paediatric clinic outpatients In a previous 6 2 58 1 1 43 22 1 4 55 21 5 17 86 21 0 0 00 21 0 0 00 21 1 4 55 21 2 9 09 21 0 0 00 21 10 1 38 This study 57 6 22 This study 2 1 75 This study 1 0 86 23 11 10 38 23 28 9 33 18 4 2 00 This study 33 3 29 15 till July 2000 study we noticed that HCoV NL63 infection is observed more fre quently in outpatients 10 and here we calculated that it reflects almost 17 000 visits to the paediatrician each year in Germany whereas less than 600 children under the age of 3 years need to be hospitalized There are only 2 previous studies that calculated the incidence of HCoV NL63 infection one from Hong Kong and one from Nashville USA 12 24 The Hong Kong study noticed high numbers of hospital izations due to HCoV NL63 infection 210 hospital admissions per 100 000 children 6 years of age whereas we estimate 22 hospi talizations per 100 000 children below the age of 3 The difference in age of the test populations is unlikely to explain the difference We think that other reasons are more significant In the Hong Kong study all HCoV NL63 children were included regardless of the viral load in the NPA or the presence of a second infection Furthermore only a single year was monitored in Hong Kong and we noticed that the incidence of HCoV NL63 displays year to year differences with a 3 4 times higher rate in uneven winters in Western Europe We did not include any double infections and HCoV NL63 infections with low viral load to diminish the chance that children who are ill due to another respiratory virus infection are counted In addition it cannot be ruled out that we even missed some double infections since our samples were not tested for all respiratory pathogens e g hMPV human bocavirus and rhinoviruses The Nashville study included children with LRTI from several years and a high incidence of HCoV NL63 in the 6 23 months age group was observed 12 3 HCoV NL63 associated LRTIs per 1000 children although the number of samples that were tested was small only 5 positives of the 119 samples analyzed 12 These data are in concordance with our findings as most of the children in their study were not hospitalized therefore the incidence numbers are comparable to what we noticed for outpatients 7 per 1000 children The periodicity of infection that we observed is not unexpected Already in the mid 1970s Monto 1 1467 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