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.

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.

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.

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.

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.

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.

Shiga toxin-producing Escherichia coli serotype O78:H(-) in family, Finland, 2009.

Shiga toxin-producing Escherichia coli (STEC) is a pathogen that causes gastroenteritis and bloody diarrhea but can lead to severe disease, such as hemolytic uremic syndrome (HUS). STEC serotype O78:H(-) is rare among humans, and infections are often asymptomatic. We detected a sorbitol-fermenting STEC O78:H(-):stx(1c):hlyA in blood and fecal samples of a 2-week-old boy who had bacteremia and HUS and in fecal samples of his asymptomatic family members. The phenotypic and genotypic characteristics and the virulence properties of this invasive STEC were investigated. Our findings demonstrate that contrary to earlier suggestions, STEC under certain conditions can invade the human bloodstream. Moreover, this study highlights the need to implement appropriate diagnostic methods for identifying the whole spectrum of STEC strains associated with HUS.

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.

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.

Isolation and characterization of Streptococcus mitis from blood of child with osteomyelitis.

OBJECTIVES: Osteomyelitis is an inflammatory process accompanied by bone destruction that is caused by bacterial infection, with most child cases showing a haematogenous origin and metaphysis of the long bones. The aim of the present study was to characterize streptococcal strains isolated from the blood of a child diagnosed with osteomyelitis in a long bone and investigate the biological properties related to virulence of strains associated with osteomyelitis. METHODS: Blood isolate species were determined based on the 16S rRNA sequence. Next, the blood isolates were analysed for phagocytosis susceptibility by polymorphonuclear leukocytes, platelet aggregation, inhibitory effects on osteoblastic cells, and their properties of adhesion with cells, and compared to the reference strain Streptococcus mitis ATCC49456. RESULTS: The blood isolates were found to be a single clone (named SA1101), which was determined to be S. mitis. The phagocytosis susceptibility of SA1101 was significantly lower than that of ATCC49456, while its platelet aggregation rate was higher. Furthermore, SA1101 showed an inhibitory effect toward the growth of osteoblastic cells and had greater properties of adhesion to those cells as compared to ATCC49456. CONCLUSIONS: These results suggest that S. mitis SA1101 is a possible etiological agent and caused osteomyelitis in the present case.

[Lymphadenitis caused by nontuberculous mycobacteriae]. / Lasten atyyppiset mykobakteeri-infektiot lisääntyvät.

Lymphadenitis caused by nontuberculous mycobacteriae has been increasingly seen in Finland since the cessation of universal BCG vaccination in 2006. An otherwise healthy child develops a slowly growing unilateral mass in the cervicofacial region. Without treatment, the lymphadenitis suppurates and forms a draining sinus, which dries after some weeks or months, leaving a scar. Surgical excision is curative treatment but cannot always be performed because of risk to the facial nerve or need of extensive surgery. In these cases, observation without antimicrobial treatment is usually recommended. The parents need professional information and support.

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.

Pneumococcal serotype distribution in invasive paediatric disease in Southern Finland before the introduction of vaccine.

Vaccination with pneumococcal conjugate vaccines (PCV) has been started in many countries, resulting in a marked decrease in the incidence of invasive pneumococcal disease (IPD). After the decline, an increase in the incidence of IPD caused by non-vaccine serotypes has been observed. Finland has just decided to incorporate PCV into the national immunization programme, starting 1 September 2010. We describe the patients treated for IPD in one hospital in Finland before the use of PCV. Details of patients treated for IPD at the Children's Hospital, University of Helsinki between 2002 and 2007, were sought using the hospital discharge register and laboratory data. In total 118 cases of IPD were diagnosed in 113 children between 1 January 2002 and 31 December 2007. The yearly number of cases of IPD increased from 10 in 2002 to 26 in 2007. There were 5 deaths, all in patients with meningitis (5/19, 26%), and the total mortality was 4% (5/113). Seventy-five (77%) of the 97 pneumococcal isolates for which serotype was available were covered by the 7-valent PCV; 77% were also in the 10-valent PCV and 91% in the 13-valent PCV. Considering the serotype distribution of the pneumococcal isolates, a marked benefit is expected from including PCV in the vaccination programme.

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.

Differential diagnosis of acute central nervous system infections in children using modern microbiological methods.

AIM: Except bacterial meningitis, the agents causing acute central nervous system (CNS) infections in children are disclosed in only approximately half of the cases, and even less in encephalitis. We studied the potential of modern microbiological assays to improve this poor situation. METHODS: In a prospective study during 3 years, all children attending hospital with suspected CNS infection were examined using a wide collection of microbiological tests using samples from the cerebrospinal fluid, serum, nasal swabs and stool. RESULTS: Among 213 patients, 66 (31%) cases suggested CNS infection and specific aetiology was identified in 56 patients. Of these microbiologically confirmed cases, viral meningitis/encephalitis was diagnosed in 25 (45%), bacterial meningitis in 21 (38%) and neuroborreliosis in 9 (16%) cases while 1 child had fungal infection. In meningitis patients, the causative agent was identified in 85% (35/41) cases and in encephalitis in 75% (12/16). The most common bacteria were Streptococcus agalactiae, Streptococcous pneumonie and Neisseria meningitidis, while the most frequently detected viruses were enteroviruses and varicella zoster virus. CONCLUSION: In 75% to 85% of paediatric CNS infections, specific microbiological diagnosis was obtained with modern laboratory techniques. The results pose a basis for prudent approach to these potentially serious diseases.

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.

Similarities of Kawasaki disease and Yersinia pseudotuberculosis infection epidemiology.

Although an infectious etiology is strongly suspected in Kawasaki disease (KD), an etiologic agent has not yet been identified. By reviewing epidemiologic data published in past decades, this work highlights a higher incidence of KD when populations were exposed to the risk of Yersinia pseudotuberculosis infection. This hitherto unnoticed element reinforces the hypothesis whereby this bacterium might contribute to the development of KD in some cases.