How many of persistent coughers have pulmonary tuberculosis? Populationbased cohort study in Ethiopia

Objective Many individuals with persistent cough and smear microscopy-negative sputum test for tuberculosis (TB) remain at risk of developing the disease. This study estimates the incidence of pulmonary TB (PTB) among initially smear-negative persistent coughers and its risk factors. Design A prospective population-based follow-up study. Setting Health extension workers visited all households in Dale woreda three times at 4-month intervals in 2016–2017 to identify individuals with symptoms compatible with TB (presumptive TB) using pretested and semistructured questionnaires. Participants We followed 3484 presumptive TB cases (≥15 years) with an initial smear-negative TB (PTB) test. Outcome measures Bacteriologically confirmed PTB (PTB b+) and clinically diagnosed PTB (PTB c+). Results 3484 persons with initially smear-negative presumptive PTB were followed for 2155 person-years (median 0.8 years); 90 individuals had PTB b+ and 90 had PTB c+. The incidence rates for PTB b+ and PTB c+ were both 4176 (95% CI 3378 to 5109) per 100 000 person-years. We used penalised (lasso) and non-penalised proportional hazards Cox regression models containing all exposures and outcomes to explore associations between exposures and outcomes. In lasso regression, the risk of development of PTB b+ was 63% (HR 0.37) lower for people aged 35–64 years and 77% (HR 0.23) lower for those aged ≥65 years compared with 15–34 year-olds. Men had a 62% (HR 1.62) greater risk of PTB b+ development than women. The risk of PTB c+ was 39% (HR 0.61) lower for people aged 35–54 years than for those aged 15–34 years. Men had a 56% (HR 1.56) greater risk of PTB c+ development than women. Conclusions PTB incidence rate among persistent coughers was high, especially among men and young adults, the latter signifying sustained transmission. Awareness about this among healthcare workers may improve identification of more new TB cases.publishedVersio

Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study

Background: Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016. Methods: This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson’s chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects. Results: We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals. Conclusions: We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.publishedVersio

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

The risk of invasive pneumococcal disease differs between risk groups in Norway following widespread use of the 13-valent pneumococcal vaccine in children

The elderly and adults with medical risk conditions remain at high risk of invasive pneumococcal disease (IPD), highlighting the importance of adequate preventive efforts. In an observational population-based study in Norway (pop ≥ 5 years, 2009–2017) covering six years post-PCV13 implementation, we explored the incidence and risk of IPD associated with age and comorbidities. We obtained the data on 5535 IPD cases from the Norwegian Surveillance System for Communicable Diseases and the population data from Statistics Norway. To define comorbidities, we obtained ICD-10 codes from the Norwegian Patient Registry for the cases and the Norwegian population. The average annual decrease in PCV13 IPD incidence was significant in all risk groups and decreased post-PCV13 introduction by 16–20% per risk group, implying a nondifferential indirect protection from the childhood vaccination. The IPD incidence remained high in the medical risk groups. The relative importance of medical risk conditions was 2.8 to 6 times higher in those aged 5–64 versus ≥65 years for all types of IPD, since age itself is a risk factor for IPD. In groups without medical risk, the risk of IPD was eight times higher in those aged ≥65 compared to those 5–64 years (RR 8.3 (95% CI 7.3–9.5)). Our results underscore the need for age- and risk-group-based prevention strategies

Measles vaccine coverage among children born to Somali immigrants in Norway

Abstract Background Despite overall good vaccination coverage in many countries, vaccine hesitancy has hindered full coverage and exposed groups to the risk of outbreaks. Somali immigrant groups have been known to have low measles vaccination coverage, leading to outbreaks in their communities. Current research indicates a general lack of trust in the healthcare system, the use of alternative information sources and inadequate health literacy can be contributing factors. We explore measles vaccine coverage in children born to Somali parents in Norway, whether it has changed over time and factors that may influence coverage. Methods Data was extracted from the National Population Register on all children born in Norway from 2000 to 2016, where both parents originated from Somalia. Date of birth, gender, residential area at birth and date of immigration and emigration for both parents was linked to information on measles vaccination from the National Immunisation Register. Results We found that children born to Somali immigrants in Norway had suboptimal measles vaccine coverage at 2 years; for children born in 2016 the coverage was 85%. Coverage declined between 2000 and 2016, and at a greater rate for boys than girls. Children born to mothers residing in Norway for 6 years or more had lower coverage compared to those with mothers residing less than 2 years prior to their birth. Children born in the capital and surrounding county had significantly lower coverage than children born elsewhere in Norway. Discussion New targeted interventions are needed to improve measles vaccine coverage among Somali immigrants in Norway. Some possible strategies include using Somali social media platforms, improving communication with Somali parents and tighter cooperation between various countries’ vaccination programmes

Feasibility of reaching world health organization targets for hepatitis C and the cost‐effectiveness of alternative strategies

New drugs for treating hepatitis C have considerably increased the probability of being cured. Treatment uptake, however, is still low. The objectives of this study were to analyse the impact of initiatives that may increase the proportion of infected people on treatment and interventions aimed at reducing the incidence of new infection among people who inject drugs. A compartmental model for Norway was used to simulate hepatitis C and related complications. We analysed 2 different screening initiatives aimed to increase the proportion of infected people on treatment. Interventions aiming at reducing the hepatitis C incidence analysed were opioid substitution therapy (OST), a clean needle and syringe programme and a combination of both. The most cost‐effective strategy for increasing hepatitis C treatment uptake was screening by general practitioners while simultaneously allowing for all infected people to be treated. We estimated that this intervention reduces the incidence of hepatitis C by 2030 by 63% compared with the current incidence. The 2 harm reduction strategies both reduced the incidence of hepatitis C by about 70%. Combining an increase in the current clean needles and syringe programme with OST was clearly the most cost‐effective option. This strategy would reduce the incidence of hepatitis C by 80% compared with the current incidence by 2030. Thus, interventions to reduce the burden and spread of hepatitis C are cost‐effective. Reaching the WHO target of a 90% reduction in hepatitis C incidence by 2030 may be difficult without combining different initiatives

Immigrant screening for latent tuberculosis infection: numbers needed to test and treat, a Norwegian population-based cohort study

Objectives: To estimate the number needed to screen (NNS) and the number needed to treat (NNT) to prevent one tuberculosis (TB) case in the Norwegian immigrant latent tuberculosis infection (LTBI) screening programme and to explore the effect of delay of LTBI treatment initiation. Methods: We obtained aggregated data on immigration to Norway in 2008–2011 and used data from the Norwegian Surveillance System for Infectious Diseases to assess the number of TB cases arising in this cohort within 5 years after arrival. We calculated the average NNS and NNT for immigrants from the top 10 source countries for TB in Norway and by estimated TB incidence rates in source countries. We explored the sensitivity of these estimates with regard to test performance, treatment efficacy and treatment adherence using an extreme value approach, and assessed the effects of emigration, time to TB diagnosis (to define incident TB) and intervention timing. Results: NNS and NNT were overall high, with substantial variation. NNT showed numerically stronger negative correlation with TB notification rate in Norway (−0.75 [95% CI −1.00 to −0.44]) than with the WHO incidence rate (IR) (−0.32 [95% CI −0.93 to 0.29]). NNT was affected substantially by emigration and the definition of incident TB. Estimates were lowest for Somali (NNS 99 [70–150], NNT 27 [19–41]) and highest for Thai immigrants (NNS 585 [413–887], NNT 111 [79–116]). Implementing LTBI treatment in immigrants sooner after arrival may improve the effectiveness of the programme. Conclusion: Using TB notifications in Norway, rather than IR in source countries, would improve targeting of immigrants for LTBI management. However, the overall high NNT is a concern and challenges the scale-up of preventive LTBI treatment for significant public health impact. Better data are urgently needed to monitor and evaluate NNS and NNT in countries implementing LTBI screening