Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Brain white matter hyperintensities in Kawasaki disease: A case-control study.

Background: Cerebrovascular involvement of Kawasaki disease (KD) is poorly studied. White matter hyperintensities (WMH) indicate cerebral small vessel disease and increase the risk for stroke. Purpose: To investigate whether childhood KD is associated with WMHs and other cerebrovascular findings later in adulthood. Materials and methods: In this case-control study, patients diagnosed with KD (cases) at our tertiary hospital between 1978 and 1995 were invited to brain magnetic resonance (MRI) between 2016 and 2017. Migraine patients (controls) with available brain MRI were matched with cases (ratio 4:1) by age (±2 years) and sex. Two blinded neuroradiologists evaluated independently cerebrovascular findings from the brain MRI scans. Modified Scheltens' visual rating scale was used to evaluate WMH burden and the total WMH volume was measured using manual segmentation. Results: Mean age [years, (SD)] at the time of brain MRI was 33.3 (3.8) and 32.8 (4.0) for cases (n = 40) and controls (n = 160), respectively (P = 0.53). Mean follow-up time for cases was 29.5 years (4.3). Total volume of WMHs (median) was 0.26 cm3 (IQR 0.34) for cases and 0.065 cm3 (IQR 0.075) for controls, P = 0.039. Cases had higher total WMH burden (P = 0.003), deep WMH burden (P = 0.003), and more periventricular WMHs (prevalence 7.5 vs. 0%, P = 0.008) than controls. Cases had greater risk of having total Scheltens' score ≥2 vs. < 2 (odds ratio, 6.88; 95% CI: 1.84-25.72, P = 0.0041) and ≥3 vs. < 3 (odds ratio, 22.71; 95% CI: 2.57-200.53, P = 0.0049). Diabetes type 1/type 2, hypertension, smoking status or hypercholesterolemia were not risk factors for WMH burden, p > 0.1. Myocarditis at the acute phase of KD increased the risk for periventricular WMHs (P < 0.05). Three cases (7.5%) and three controls (1.9%) had lacune of presumed vascular origin (P = 0.0096). Conclusion: History of KD could be associated with an increased WMH burden. More studies are needed to confirm our results.

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

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 targeted.

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

IntroductionIn 2006, the Bacillus Calmette-Guérin (BCG) vaccination policy in Finland changed from universal to selective.AimWe assessed the impact of the policy change on tuberculosis (TB) morbidity in children under 5 years and epidemiological trends of paediatric TB in Finland.MethodsWe 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.ResultsWe 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): 0.7-2.3). TB rate in the native population under 15 years increased slightly (IRR = 1.06; 95% CI: 1.01-1.11).DiscussionPaediatric 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.

Epidemiology of Kawasaki disease before and after universal Bacille Calmette-Guérin vaccination program was discontinued.

AIM: Bacille Calmette-Guérin (BCG) vaccine (BCG) has been suggested to induce the primary immunity needed for the subsequent Kawasaki disease (KD). We studied the epidemiology of KD before and after the universal BCG vaccination ended in Finland in September 2006. METHODS: Kawasaki disease cases were retrieved from national health registries from 1996 to 2016 for annual incidence rates. We then compared 612 433 children born in the BCG vaccination era, from 1 January 1996 to 30 August 2006, to 604 163 born after BCG era, from 1 September 2006 to 31 December 2016. RESULTS: The annual incidence rates did not change after the BCG vaccination stopped. We found 370 first visits for KD by children born in the BCG era and 341 after universal BCG vaccination ended. The mean age at diagnosis increased from 2.6 years to 3.0 years (95% CI-0.64 to -0.012, P = .04) and the proportion of children with Kawasaki disease under 5 years decreased from 87% to 81% (95% CI 1%-12%, P = .02). CONCLUSION: Discontinuing the universal BCG vaccination programme did not change the incidence rates of KD. The increased age at diagnosis could suggest that the pathogenesis of KD may be associated with the immunological pathways primed by BCG immunisation.

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.

Unlikely association between Kawasaki disease and intracranial aneurysms: a prospective cohort study.

OBJECTIVEKawasaki disease (KD) is a vasculitis that can cause aneurysm formation in coronary arteries and, more rarely, in peripheral arteries. A possible connection between KD and intracranial aneurysms is unclear. The purpose of this study was to determine if KD is associated with intracranial aneurysms.METHODSIn this prospective cohort study, all patients hospitalized and diagnosed with KD in the authors' hospital district area in the period from 1978 to 1995 were identified. Patients with a current age ≥ 25 years and a history of KD in childhood were included in the study, which was conducted between 2016 and 2017. Magnetic resonance angiography (MRA) of the brain was performed in all patients.RESULTSForty patients (25 males), whose mean age was 33.5 ± 3.9 years (mean ± standard deviation), were eligible for study inclusion. The mean age at KD diagnosis was 3.9 ± 3.1 years, and the mean follow-up was 29.5 ± 4.3 years. Six patients (15%) had coronary arterial lesions during the acute illness of KD. None of the patients (0%) had intracranial aneurysms on brain MRA, which is significantly under the prevalence of 10% (95% CI 0%-8.8%, p = 0.03) that is the recommended limit for intracranial aneurysm screening.CONCLUSIONSThe study results suggest that KD is not associated with an increased prevalence of intracranial aneurysms and that screening for intracranial aneurysms is not warranted in patients with a history of KD.

Increase in Childhood Nontuberculous Mycobacterial Infections After Bacille Calmette-Guérin 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-Guérin (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 <5 years infected with NTM (median age, 27 months; female-to-male ratio, 2:1). The most common species was Mycobacterium avium (n = 69 [71%]). The estimated incidence rates of NTM in universal-BCG and selective-BCG cohorts were 0.2 and 3.9 per 100000 person-years, respectively. The incidence rate ratio of selective-BCG cohorts compared to universal-BCG cohorts was 19.03 (95% confidence interval, 8.82-41.07; P < .001). 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. This observation adds to the understanding of childhood NTM epidemiology and might explain why the disease is emerging in some countries.

The impact of Bacille Calmette-Guérin 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.

Elispot Igra With Purified Protein Derivative Stimulation For Diagnosing Nontuberculous Mycobacterial Cervical Lympadenitis.

Childhood cervical lymphadenitis caused by nontuberculous mycobacteria is a diagnostic challenge for the clinician. We present a new promising diagnostic method for childhood nontuberculous mycobacterial lymphadenitis. The modified T-SPOT.TB test with purified protein derivative as an additional antigen is noninvasive with estimated sensitivity and specificity of 1.00 and 0.81, respectively.

Finnish guidelines for the treatment of laryngitis, wheezing bronchitis and bronchiolitis in children.

UNLABELLED: Evidence-based guidelines are needed to harmonise and improve the diagnostics and treatment of children's lower respiratory tract infections. Following a professional literature search, an interdisciplinary working group evaluated and graded the available evidence and constructed guidelines for treating laryngitis, bronchitis, wheezing bronchitis and bronchiolitis. CONCLUSION: Currently available drugs were not effective in relieving cough symptoms. Salbutamol inhalations could relieve the symptoms of wheezing bronchitis and should be administered via a holding chamber. Nebulised adrenaline or inhaled or oral glucocorticoids did not reduce hospitalisation rates or relieve symptoms in infants with bronchiolitis and should not be routinely used.

Invasive Group A Streptococcal Infections in Children: A Nationwide Survey in Finland.

BACKGROUND: The incidence of invasive group A streptococcus (iGAS) infections varies in time and geographically for unknown reasons. We performed a nationwide survey to assess the population-based incidence rates and outcomes of children with iGAS infections. METHODS: We collected data on patients from hospital discharge registries and the electronic databases of microbiological laboratories in Finland for the period 1996-2010. We then recorded the emm types or serotypes of the strains. The study physician visited all university clinics and collected the clinical data using the same data entry sheet. RESULTS: We identified 151 children with iGAS infection. Varicella preceded iGAS infection in 20% of cases and fasciitis infection in 83% of cases. The annual incidence rate of iGAS infection was 0.93 per 100,000 in 1996-2000, 1.80 in 2001-2005 and 2.50 in 2006-2010. The proportion of emm 1.0 or T1M1 strains peaked in 1996-2000 and again in 2006-2010, to 44% and 37% of all typed isolates. The main clinical diagnoses of the patients were severe soft-tissue infection (46%), sepsis (28%), empyema (10%), osteoarticular infection (9%) and primary peritonitis (5%). Severe pain was the most typical symptom for soft-tissue infections. More than half of the patients underwent surgery and received clindamycin. The readmission rate was 7%, and the case fatality rate was 2%. CONCLUSIONS: The incidence rate of pediatric iGAS infections tripled during our study. The increase was not, however, the result of a change in the strain types causing iGAS. Varicella immunization would likely have prevented a significant number of the cases.

Finnish guidelines for the treatment of community-acquired pneumonia and pertussis in children.

UNLABELLED: Evidence-based guidelines are needed to harmonise and improve the diagnostics and treatment of children's lower respiratory tract infections. Following a professional literature search, an interdisciplinary working group evaluated and graded the available evidence and constructed guidelines for the treatment of community-acquired pneumonia and pertussis. CONCLUSION: The clinical guidelines state that chest radiography is not needed if the child is diagnosed with pneumonia and treated at home. Complications should be considered if there is no improvement after antimicrobial therapy and a paroxysmal cough can indicate pertussis, which is life-threatening in unvaccinated infants and can lead to respiratory failure.

Retropharyngeal involvement in Kawasaki disease--a report of four patients with retropharyngeal edema verified by magnetic resonance imaging.

Kawasaki disease is an acute systemic vasculitis of childhood. The diagnosis is based on clinical criteria. Prognosis with adequate treatment is favorable. Untreated patients, however, may develop coronary manifestations predisposing to acute myocardial infarction. Retropharyngeal edema is a rare but known manifestation of Kawasaki disease. We present a case series of four Kawasaki patients presenting with clinical findings for retropharyngeal abscess and the magnetic resonance imaging findings of these patients, diagnosed during a six week period. To our knowledge, this is the first systematic report of cervical MRI findings of Kawasaki patients.

An outbreak of CTX-M-15 -producing Escherichia coli, Enterobacter cloacae, and Klebsiella in a children's hospital in Finland.

Four different extended-spectrum ß -lactamase (ESBL)-producing bacteria from a pediatric surgery ward were studied. The presence of TEM-, SHV-, and CTX-M-type ß -lactamases was analyzed and the relatedness of the isolates studied with a repetitive PCR system (DiversiLab) and pulsed-fi eld gel electrophoresis (PFGE). Molecular analysis showed that a clonal dissemination of CTX-M-15-producing Escherichia coli and Enterobacter cloacae had occurred.

Inclusion of latent tuberculosis infection as a separate entity into the international classification of diseases.

The 11th revision of the International Classification of Diseases (ICD-11) proposed by the WHO is currently in the consultation phase. In common with previous versions of the ICD this revised version does not contain a code for latent tuberculosis infection (LTBI), contrasting with the inclusion of a large number of codes for various manifestations of active tuberculosis (TB). Inclusion of a separate code for LTBI into ICD-11 is critically important for epidemiological, clinical and research purposes. On behalf of the Paediatric Tuberculosis Network European Trials group, we encourage colleagues worldwide who are caring for TB patients or are involved in TB research to join us in supporting the case for a long overdue ICD code for LTBI.

Evaluation of the filter paper IP-10 tests in school children after exposure to tuberculosis: a prospective cohort study with a 4-year follow-up.

OBJECTIVES: The prevalence of active tuberculosis (TB) is low in Finland, but outbreaks do occur. Following exposure national guidelines recommend either tuberculosis skin test or interferon-γ-release assay-testing of asymptomatic children. The aim of this study was to compare QuantiFERON-TB Gold In-Tube test (QFT) and interferon-γ-inducible protein (IP-10) release assay for detection of Mycobacterium tuberculosis infection following exposure to TB in a primary school. DESIGN: A prospective cohort study. SETTING: School children in Helsinki, Finland. PARTICIPANTS: Two siblings of the index case and 58 classmates exposed to M tuberculosis. INTERVENTION: All the children were screened using the QFT, which was used to guide preventive treatment. All those exposed were followed up through the national TB registry. OUTCOME MEASURES: IP-10 was measured in plasma supernatants from the QFT test supernatants and in plasma dried and stored for 1 year on filter paper. IP-10 test results were calculated using preset algorithms for positive and indeterminate tests. The negative predictive values of the tests were assessed. RESULTS: At an initial screening 2 months after the debut of symptoms in the index case, QFT was positive in two children; 56 tests were negative; one was indeterminate and one was borderline. IP-10 showed a perfect concordance between the dried plasma spot and plasma method; two children were IP-10 positive and two were IP-10 indeterminate. There were two (3%) discordant results between the QFT and IP-10 tests. Four children converted to positive QFT at a 1-3 month follow-up. None of the QFT negative/borderline children developed TB in the 4-year period since exposure. CONCLUSIONS: We demonstrated that IP-10 and QFT perform comparably as screening tools for infection with M tuberculosis in a contact investigation. IP-10 determined in dried plasma spots was at par with IP-10 determined in plasma, which further supports the usefulness of this alternative approach.

Incidence of Kawasaki disease in northern European countries.

BACKGROUND: The aim of the present study was to compare the epidemiologic features of Kawasaki disease (KD) in three northern European countries and Japan. METHODS: Data were obtained from discharge databases for hospitals in Finland, Norway, and Sweden for 1999-2009 and from nationwide epidemiologic surveys in Japan for 1998-2008. Annual incidence for each country was calculated using regional census data. RESULTS: During the 11 year period, 1390 KD patients were recorded in the registries of the three northern European countries. Average annual incidence rates per 100,000 children aged <5 years were: Finland, 11.4; Norway, 5.4; and Sweden, 7.4. Overall, 86.4% of Japanese KD patients were aged <5 years compared to only 67.8% in the four northern European countries (P < 0.001). CONCLUSIONS: The incidence of KD in northern Europe was constant over the study period and much lower than in Japan. There was a significant age difference between northern European and Japanese KD patients that remains unexplained.