Bacille Calmette-Guérin Vaccination Policy Change and Childhood Mycobacterial Infections in Finland

The World Health Organization declared tuberculosis (TB) a global emergency over 25 years ago, yet TB remains a significant public health concern and a leading infectious killer of our time. Young children are especially vulnerable to rapid and debilitating TB disease, and infected children should be identified and therapy initiated rapidly. Nontuberculous mycobacteria (NTM) infections have also emerged in Western countries. Childhood NTM infections predominantly manifest as prolonged cervical lymphadenitis, which is a diagnostic challenge for the clinician due to the limitations of NTM cultures. Bacille Calmette-Guérin (BCG) vaccine effectively prevents severe TB disease forms in young children. Some studies have further suggested that BCG might also offer protection against childhood NTM infections. In Finland, BCG coverage of infants was very high until the vaccination policy changed in 2006 to a risk group-based approach. Subsequently, for the first time since the 1940s, a generation of children has grown in Finland without the protection of BCG against mycobacterial diseases. Furthermore, the healthcare and national surveillance registries allowing retrospective evaluation of TB and NTM cases in Finland are exceptional and provide a rare look into paediatric TB and NTM epidemiology with or without universal BCG vaccinations. In addition, a novel in-house diagnostic test developed in the Hospital District of Helsinki and Uusimaa (HUS) laboratory has shown potential in childhood NTM lymphadenitis diagnostics but has not been evaluated. In the first study, we evaluated the performance of the novel modified T.SPOT.TB test in children under five years of age with culture-confirmed NTM lymphadenitis and compared the results to a control group of healthy children. The estimated sensitivity and specificity of the modified T-SPOT.TB test were 1.00 and 0.81, respectively. The modified T.SPOT. TB was a promising noninvasive diagnostic test for childhood NTM lymphadenitis. In the second study, we identified native-born children aged 0–4 years infected with NTM between 1995 and 2016 from the Finnish National Infectious Diseases Register (NIDR) and estimated the NTM incidence rate change between birth cohorts born during universal or selective BCG vaccination policy. We identified 97 native-born children infected with NTM under the age of five. The estimated incidence rates of NTM in universal-BCG and selective-BCG cohorts were 0.2 and 3.9 per 100,000 person-years, respectively. The incidence rate ratio (IRR) of selective-BCG cohorts compared to universal-BCG cohorts was 19.03 (95% confidence interval [CI], 8.82–41.07). Childhood NTM infections increased drastically after the infant BCG coverage decreased, suggesting that BCG offers protection against childhood NTM lymphadenitis. In the third study, we identified all newly diagnosed active TB cases under 15 years of age in Finland 1995–2015 by linking data from the NIDR, Finnish Care Register for Health Care, medical patient records, and Finnish Population Information System. We compared the under-five TB incidence rate ratio of birth cohorts with universal and selective BCG vaccinations. We identified a total of 139 paediatric TB cases. The under-five TB rate of birth cohorts with selective-BCG compared to birth cohorts with universal-BCG remained stable (IRR 1.3; 95% CI, 0.7–2.3). Paediatric TB in Finland was concentrated in families with an immigrant background from high TB incidence countries. The native under-five TB morbidity did not increase after the BCG vaccination policy change in Finland, suggesting that well-implemented selective vaccinations can prevent TB in the most vulnerable age group effectively in low-incidence settings. In the fourth study, we retrospectively reviewed paediatric TB contact tracing results from 2012 to 2016 in the HUS area. The yield for TB disease or infection was 4.6% and 12.8% for household contacts, 0.5% and 0% for contacts exposed in a congregate setting, and 1.4% and 5.0% for other contacts, respectively. Contact tracing in the HUS area identified exposed young children quickly: most of the TB infections among the children under five years of age were found before progression to disease, and none had severe disease forms. The maximum delay until the first contact investigation visit among the household contacts under five years of age with either TB disease or infection was seven days from the index case diagnosis. Contacts born in a TB endemic country (adjusted odds ratio [aOR] 3.07; 95% CI, 1.10–8.57), with household exposure (aOR 2.96; 95% CI, 1.33–6.58), or a sputum smear-positive index case (aOR 3.96; 95% CI, 1.20–13.03) were more likely to have TB disease or infection. The yield for TB disease or infection of large-scale investigations after exposure in a congregate setting was very low, and investigations in such events should be cautiously targeted. In summary, the epidemiological landscape of childhood mycobacterial infections in Finland has changed. The BCG vaccination policy change in 2006 resulted in an increase in childhood NTM infections, but childhood TB infections did not increase, and restarting universal BCG vaccinations seems unwarranted. Childhood TB, however, remains an essential public health issue, and future surveillance is vital. The focus of childhood TB prevention in Finland should be further targeted to those with an immigrant background from high TB burden countries.Maailman terveysjärjestö WHO julisti tuberkuloosin kansainväliseksi terveydelliseksi hätätilanteeksi jo yli 25 vuotta sitten, mutta tuberkuloosi on edelleen yksi merkittävimmistä infektiotaudeista ja kansanterveydellisistä haasteista maailmassa. Pienet lapset ovat erityisen alttiita nopealle ja vakavalle tuberkuloositaudille. Tästä syystä infektion saaneet lapset tulisi löytää nopeasti ja heidän hoitonsa aloittaa viipymättä. Ympäristömykobakteeri-infektiot ovat yleistyneet länsimaissa. Lapsilla ympäristömykobakteeri-infektiot ilmenevät yleensä kaulan tai kasvojen alueen imusolmuketulehduksina, joiden diagnostiikka bakteeriviljelyn avulla on haasteellista. Tuberkuloosi- eli BCG-rokotukset ehkäisevät tehokkaasti pienten lasten vakavia tuberkuloositautimuotoja, ja ne saattavat myös ehkäistä lapsuuden ympäristömykobakteeri-infektiota. Suomessa BCG-rokotuskattavuus oli erittäin hyvä rokotusohjelman muutokseen saakka: vuonna 2006 siirryttiin rokottamaan vain korkean tuberkuloositartunnan riskiryhmiin kuuluvia lapsia. Muutoksen seurauksena Suomessa on kasvanut uusi BCG-rokottamattomien lasten sukupolvi ensimmäistä kertaa sitten 1950-luvun. Suomalaiset terveydenhuoltorekisterit mahdollistavat lasten mykobakteeri-infektioiden ilmaantuvuuden tarkastelun yleisten BCG-rokotusten aikana ja näiden jälkeen. Helsingin ja Uudenmaan sairaanhoitopiirin (HUS) laboratorio on myös kehittänyt uuden testin, jota voidaan hyödyntää lasten ympäristömykobakteerien aiheuttamien imusolmuketulehdusten diagnostiikassa, mutta testin herkkyyttä tai tarkkuutta ei ole arvioitu. Ensimmäisessä tutkimuksessa tarkasteltiin muunnellun T.SPOT.TB testin tuloksia alle 5-vuotiailla lapsilla, joilla oli todettu viljelyvarmennettu ympäristömykobakteerin aiheuttama imusolmuketulehdus, ja testituloksia verrattiin terveeseen verrokkiryhmään. Testin arvioitu herkkyys (1.00) ja tarkkuus (0.81) olivat lupaavia ympäristömykobakteerien aiheuttamien lasten imusolmuketulehduksen diagnostiikassa. Toisessa tutkimuksessa valtakunnallisesta tartuntatautirekisteristä haettiin kaikki vuosina 1995–2016 ilmoitetut alle 5-vuotiaiden lasten ympäristömykobakteeri-infektiot. BCG-rokotusohjelman muutosta ennen ja tämän jälkeen syntyneiden syntymäkohorttien ympäristömykobakteeri-infektioiden ilmaantuvuutta verrattiin keskenään. Suomessa syntyneillä lapsilla todettiin yhteensä 97 tapausta viiden vuoden ikään mennessä. Ympäristömykobakteeri-infektioiden arvioitu ilmaantuvuus ennen BCG-rokotusohjelman muutosta syntyneillä lapsilla oli 0.2/100,000 henkilövuotta ja tämän jälkeen syntyneillä lapsilla 3.9/100,000 henkilövuotta. Ilmaantuvuustiheyksien suhde oli 19.03 (95% luottamusväli, 8.82–41.07). Lasten ympäristömykobakteeri-infektiot lisääntyivät BCG-rokotusohjelman muutoksen jälkeen, mikä viittaa siihen, että BCG-rokotus ehkäisee ympäristömykobakteereiden aiheuttamia imusolmuketulehduksia lapsilla. Kolmannessa tutkimuksessa valtakunnallisen tartuntatautirekisterin, terveydenhuollon hoitoilmoitusrekisterin ja potilasasiakirjarekisterin tietoja yhdistämällä tunnistettiin Suomessa vuosina 1995–2015 alle 15-vuotiailla todetut tuberkuloositapaukset. Ennen BCG-rokotusohjelman muutosta ja tämän jälkeen syntyneiden syntymäkohorttien tuberkuloosi-ilmaantuvuutta verrattiin keskenään. Kaiken kaikkiaan alle 15-vuotiaiden tuberkuloositapauksia oli 139. Alle 5-vuotiaiden lasten tuberkuloosi-ilmaantuvuus, ennen BCG-rokotusohjelman muutosta ja tämän jälkeen syntyneillä, pysyi ennallaan (ilmaantuvuustiheyksien suhde 1.3; 95% luottamusväli, 0.7–2.3). Lasten tuberkuloositapaukset keskittyivät pääosin korkean ilmaantuvuuden maista Suomeen muuttaneisiin perheisiin. Suomessa syntyneiden alle 5-vuotiaiden tuberkuloosisairastuvuus ei lisääntynyt BCG-rokotusohjelman muutoksen jälkeen, mikä viittaa siihen, että riskiryhmiin suunnatut rokotukset ovat onnistuneet hyvin. Neljännessä tutkimuksessa käytiin läpi kaikki vuosina 2012–2016 HUS-alueen tuberkuloosin tartunnanjäljityksissä tutkitut lapset. Tuberkuloosin ja tuberkuloosi-infektion prosenttiosuudet olivat perhepiirissä altistuneilla lapsilla 4.6% ja 12.8%, joukkoaltistuksissa altistuneilla lapsilla 0.5% ja 0%, ja muilla altistuneilla lapsilla 1.4% ja 5.0%. Tartunnanjäljitys tunnisti altistuneet lapset nopeasti: valtaosa alle 5-vuotiaiden lasten infektioista löydettiin ennen taudin kehittymistä, eikä kenelläkään sairastuneista todettu vakavaa tuberkuloositautia. Tuberkuloosi-infektion saaneiden alle 5-vuotiaiden lasten viive ensimmäiseen tartunnanjäljitystutkimukseen oli enintään seitsemän vuorokautta indeksitapauksen diagnoosista. Tuberkuloosia tai infektioita todettiin erityisesti korkean tuberkuloosi-ilmaantuvuuden maassa syntyneillä (aOR 3.07; 95% CI, 1.10–8.57), samassa taloudessa altistuneilla (aOR 2.96; 95% CI, 1.33–6.58) ja yskösvärjäyspositiiviselle tuberkuloosille altistuneilla (aOR 3.96; 95% CI, 1.20–13.03). Joukkoaltistustilanteiden johdosta tutkituilla lapsilla todettiin hyvin vähän tuberkuloosi-infektioita, joten joukkoaltistumisen jälkeiset tutkimukset tulisi suunnata entistä tarkemmin. Lasten mykobakteeri-infektioiden epidemiologia on Suomessa muuttunut. BCG-rokotusohjelman muutoksen jälkeen pienten lasten ympäristömykobakteeri-infektioiden määrä on kasvanut, mutta tuberkuloosisairastuvuus ei ole lisääntynyt, joten kaikkien lasten BCG-rokotusten uudelleen aloittamiselle ei ole perusteita. Lapsuuden tuberkuloosin ennaltaehkäiseviä toimia on syytä suunnata entistä enemmän maahanmuuttajiin, jotka tulevat korkean tuberkuloosi-ilmaantuvuden maista

Increase in Childhood Nontuberculous Mycobacterial Infections After Bacille Calmette-Guerin Coverage Drop : A Nationwide, Population-Based Retrospective Study, Finland, 1995-2016

Background. Epidemiological data on childhood nontuberculous mycobacterial (NTM) disease is scarce and the protective effect of bacille Calmette-Guerin (BCG) vaccination remains debated. In 2006, the BCG policy in Finland changed from universal to selective. We aimed to study the effect of the BCG coverage decrease on the incidence of childhood NTM infections in Finland. Methods. We conducted a nationwide, population-based, retrospective study of NTM notifications recorded to the National Infectious Diseases Register between 1995 and 2016 and identified native-born children aged 0-4 years infected with NTM. Poisson log-linear model was used to estimate the change in the incidence rate of cohorts born during universal or selective BCG policy between 1995 and 2015. Results. We identified 97 native-born children aged Conclusions. After infant BCG coverage in Finland decreased, childhood NTM infections increased drastically. As there is no other apparent cause for the increase, this indicates that BCG offers protection against childhood NTM disease. 'phis observation adds to the understanding of childhood NTM epidemiology and might explain why the disease is emerging in some countries.Peer reviewe

Tuberculosis contact investigation results among paediatric contacts in low-incidence settings in Finland

Tuberculosis (TB) risk is highest immediately after primary infection, and young children are vulnerable to rapid and severe TB disease. Contact tracing should identify infected children rapidly and simultaneously target resources effectively. We conducted a retrospective review of the paediatric TB contact tracing results in the Hospital District of Helsinki and Uusimaa from 2012 to 2016 and identified risk factors for TB disease or infection. Altogether, 121 index cases had 526 paediatric contacts of whom 34 were diagnosed with TB disease or infection. The maximum delay until first contact investigation visit among the household contacts under 5 years of age with either TB disease or infection was 7 days. The yield for TB disease or infection was 4.6% and 12.8% for household contacts, 0.5% and 0% for contacts exposed in a congregate setting and 1.4% and 5.0% for other contacts, respectively. Contacts born in a TB endemic country (aOR 3.07, 95% CI 1.10-8.57), with household exposure (aOR 2.96, 95% CI 1.33-6.58) or a sputum smear positive index case (aOR 3.96, 95% CI 1.20-13.03) were more likely to have TB disease or infection. Conclusions: Prompt TB investigations and early diagnosis can be achieved with a well-organised contact tracing structure. The risk for TB infection or disease was higher among contacts with household exposure, a sputum smear positive index case or born in a TB endemic country. Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targeted. What is Known: Vulnerable young children are a high priority in contact tracing and should be evaluated as soon as possible after TB exposure What is New: Prompt investigations for paediatric TB contacts and early diagnosis of infected children can be achieved with a well-organised contact tracing structure Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targetedPeer reviewe

Paediatric tuberculosis during universal and selective Bacillus Calmette-Guerin vaccination policy : a nationwide population-based retrospective study, Finland, 1995-2015

Introduction: In 2006, the Bacillus Calmette-Guerin (BCG) vaccination policy in Finland changed from universal to selective. Aim: We assessed the impact of the policy change on tuberculosis (TB) morbidity in children under 5 years and epidemiological trends of paediatric TB in Finland. Methods: We conducted a nationwide, population-based, retrospective registry study of all newly diagnosed active TB cases younger than 15 years in Finland from 1995 to 2015 by linking data from the National Infectious Diseases Register, Finnish Care Register for Health Care, medical patient records and Finnish Population Information System. We compared the TB incidence rate ratio of under 5 year-olds with universal and selective BCG vaccinations with a Poisson log-linear model and analysed incidence trends among those younger than 15 years with a negative binomial model. Results: We identified 139 paediatric TB cases: 50 native (including 24 second-generation migrants) and 89 foreign-born children. The TB rate of under 5 year-olds remained stable after changing to selective BCG vaccination (incidence rate ratio (IRR): 1.3; 95% confidence interval (CI): 0.72.3). TB rate in the native population under 15 years increased slightly (IRR = 1.06; 95% CI: 1.01-1.11). Discussion: Paediatric TB cases in Finland were concentrated in families with migrant background from high-TB incidence countries. The native TB morbidity in under 5-year-olds did not increase after the BCG policy revision, suggesting that selective vaccinations can prevent TB in the most vulnerable age group in low-incidence settings. Second-generation migrants under 15 years in Finland with high TB risk are probably increasing.Peer reviewe

Tuberkuloosirokote vaihtuu

Tanskalaisen valmistajan tuotanto-ongelmien takia Suomessa siirrytään käyttämään japanilaista BCG-valmistetta. Haittaseurantaa varten toivotaan, että THL:lle ilmoitetaan vakavien haittojen lisäksi myös imusolmukepaiseista ja voimakkaista paikallisreaktioista

Childhood nontuberculous mycobacterial lymphadenitis –observation alone is a good alternative to surgery

Objective Cervicofacial lymphadenitis caused by nontuberculous mycobacteria (NTM) is commonly treated with surgery or antimicrobial therapy. The aim of this study was to analyze the utility of our new blood-based diagnostic method and the treatment protocol, surgery or observation alone, in NTM lymphadenitis in children. Methods All patients under 16 years of age with cervicofacial NTM lymphadenitis diagnosed and treated at Children’s Hospital or at the Department of Otorhinolaryngology, Helsinki University Hospital (Helsinki, Finland) in 2007-2017 were retrospectively reviewed. Results Fifty-two patients, 33 (63%) of whom were girls, were included in the study. The median age at initial presentation of the NTM lymphadenitis was 2.9 years. The novel blood-test had been performed on 49 (94%) of the patients and in all of them it was indicative of NTM infection. A sample for mycobacterial culture was available from 34 patients, and Mycobacterium avium was the most common species detected. Most patients (n=33, 63%) were treated conservatively with observation alone. Of these, nine patients (27%) did not develop a skin fistula, and the lymphadenitis resolved without drainage. Conclusions The novel blood test is clinically feasible method for diagnosing childhood cervicofacial NTM lymphadenitis noninvasively. Observation alone is a good alternative to surgery, without the risk of complications.Peer reviewe

Lapsen kaulapatti - milloin epäillä ympäristömykobakteeritulehdusta?

VertaisarvioituLasten ympäristömykobakteeri-infektiot ovat lisääntyneet yleisten calmetterokotusten (BCG) loputtua. Tauti ilmenee tyypillisesti pienen lapsen kaulan tai kasvojen alueen imusolmuketulehduksena. Diagnostiikan apuna voidaan käyttää kaikututkimusta ja immunologista verikoetta. Ympäristömykobakteerien aiheuttaman imusolmuketulehduksen hoidossa mikrobilääkkeistä ei ole hyötyä. Imusolmukkeen kirurgista poistoa voidaan harkita, mutta usein mitään hoitoa ei tarvita ja seuranta riittää.Peer reviewe

Ripaus kauraa tukee hernekasvuston

Herneen viljely tukikasvin kanssa vähentää lakoontumista. Yleisin tukikasvi on lujakortinen kaura. Herne ja kaura pysyvät yhdessä kauemmin pystyssä, mutta herneen osuus sadosta vähenee kilpailun vuoksi. Myös kauran varjostus vähentää palkojen ja herneiden määrää.vokKV

The impact of Bacille Calmette-Guerin shortage on immunisation practice and policies in Europe - A Paediatric Tuberculosis Network European Trials Group (ptbnet) survey

Background: Recent reports indicate an ongoing BCG shortage that may influence immunisation practice. This study aimed to determine current availability of BCG vaccine across Europe, and implications on immunisation practices and policies in Europe. Methods: Web-based survey among Paediatric Tuberculosis Network European Trials Group (ptbnet) members, between May and October 2015. Results: Twenty individuals from 13 European countries participated. Ongoing shortages were reported in eight countries routinely using BCG (8/11, 73%). As a consequence of the shortage, BCG was not given as completely unavailable in some countries (2/8, 25%), was given only whenever available (1/8,13%), or only in certain regions of the country (1/8, 13%). Strategies reported to reduce loss of immunisation were administration to selected high-risk individuals (2/8, 25%), or cohorting vaccinees on specific days to maximise the use of multi-dose vials (3/8, 38%). Authorities in two countries each were considering a change of manufacturer/supplier (2/8, 25%). Conclusions: The BCG shortage in Europe leads to significant changes in immunisation policies including changes of BCG vaccine strain and manufacturer. In addition, infants and children eligible for immunisation are at risk of not receiving BCG. To ensure necessary BCG immunisations, collaboration between national health agencies and vaccine manufacturers is crucial. (C) 2016 Elsevier Ltd. All rights reserved.Peer reviewe