Susceptibility and infectiousness of SARS-CoV-2 in children versus adults, by variant (wild-type, alpha, delta): A systematic review and meta-analysis of household contact studies.

IMPORTANCE: Understanding the susceptibility and infectiousness of children and adolescents in comparison to adults is important to appreciate their role in the COVID-19 pandemic. OBJECTIVE: To determine SARS-CoV-2 susceptibility and infectiousness of children and adolescents with adults as comparator for three variants (wild-type, alpha, delta) in the household setting. We aimed to identify the effects independent of vaccination or prior infection. DATA SOURCES: We searched EMBASE, PubMed and medRxiv up to January 2022. STUDY SELECTION: Two reviewers independently identified studies providing secondary household attack rates (SAR) for SARS-CoV-2 infection in children (0-9 years), adolescents (10-19 years) or both compared with adults (20 years and older). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data, assessed risk of bias and performed a random-effects meta-analysis model. MAIN OUTCOMES AND MEASURES: Odds ratio (OR) for SARS-CoV-2 infection comparing children and adolescents with adults stratified by wild-type (ancestral type), alpha, and delta variant, respectively. Susceptibility was defined as the secondary attack rate (SAR) among susceptible household contacts irrespective of the age of the index case. Infectiousness was defined as the SAR irrespective of the age of household contacts when children/adolescents/adults were the index case. RESULTS: Susceptibility analysis: We included 27 studies (308,681 contacts), for delta only one (large) study was available. Compared to adults, children and adolescents were less susceptible to the wild-type and delta, but equally susceptible to alpha. Infectiousness analysis: We included 21 studies (201,199 index cases). Compared to adults, children and adolescents were less infectious when infected with the wild-type and delta. Alpha -related infectiousness remained unclear, 0-9 year old children were at least as infectious as adults. Overall SAR among household contacts varied between the variants. CONCLUSIONS AND RELEVANCE: When considering the potential role of children and adolescents, variant-specific susceptibility, infectiousness, age group and overall transmissibility need to be assessed.

Inventory study on completeness of tuberculosis case notifications in Poland in 2018.

BackgroundEvaluating tuberculosis (TB) notification completeness is important for monitoring TB surveillance systems, while estimating the TB disease burden is crucial for control strategies.AimWe conducted an inventory study to assess TB reporting completeness in Poland in 2018.MethodsUsing a double-pronged inventory approach, we compared notifications of culture-positive TB cases in the National TB Register to records of diagnostic laboratories. We calculated under-reporting both with observed and capture-recapture (CRC)-estimated case numbers. We further compared the notifications by region (i.e. voivodship), sex, and age to aggregated data from hospitalised TB patients, which provided an independent estimate of reporting completeness.ResultsIn 2018, 4,075 culture-positive TB cases were notified in Poland, with 3,789 linked to laboratory records. Laboratories reported further 534 TB patients, of whom 456 were linked to notifications from 2017 or 2019. Thus, 78 (534 - 456) cases were missing in the National TB Register, yielding an observed TB under-reporting of 1.9% (78/(4,075 + 78) × 100). CRC-modelled total number of cases in 2018 was 4,176, corresponding to 2.4% ((4,176 - 4,075)/4,176 × 100) under-reporting. Based on aggregated hospitalisation data from 13 of 16 total voivodeships, under-reporting was 5.1% (3,482/(3,670 - 3,482) × 100), similar in both sexes but varying between voivodeships and age groups.ConclusionsOur results suggest that the surveillance system captures ≥ 90% of estimated TB cases in Poland; thus, the notification rate is a good proxy for the diagnosed TB incidence in Poland. Reporting delays causing discrepancies between data sources could be improved by the planned change from a paper-based to a digital reporting system.

[Treatment of MDR, pre-XDR, XDR and rifampicin resistant tuberculosis or in case of intolerance to at least rifampicin in Austria, Germany and Switzerland - Amendment dated 19.09.2023 to the Sk2-Guideline: Tuberculosis in adulthood of the German Central Committee against Tuberculosis (DZK) on behalf of the German Respiratory Society (DGP)]. / Therapie bei MDR-, prä-XDR-, XDR-Tuberkulose und Rifampicin-Resistenz oder bei Medikamentenunverträglichkeit gegenüber mindestens Rifampicin.

In December 2022, based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB). The evaluation of both, these recommendations, and the latest study data, makes it necessary to update the existing guidelines on the treatment of at least rifampicin-resistant tuberculosis for the German-speaking region, hereby replacing the respective chapters. A shortened MDR-TB treatment of at least 6 month using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Germany, Austria, and Switzerland under certain conditions. This recommendation applies to TB cases with proven rifampicin resistance, including rifampicin monoresistance. For treatment of pre-extensively drug resistant TB (pre-XDR-TB), an individualized treatment for 18 months adjusted to resistance data continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in pre-XDR TB if all prerequisites are met. The necessary prerequisites for the use of BPaLM and BPaL are presented in this amendment to the S2k guideline for 'Tuberculosis in adulthood'.

[Tuberculosis Infection Control & Hygiene - Recommendations of the DZK]. / Infektionsprävention & Hygiene bei Tuberkulose ­ Empfehlungen des DZK.

Preventing the spread of the disease is an essential goal in the care and treatment of tuberculosis. In addition to early diagnosis and effective therapies, isolation of infectious patients and adequate hygiene measures are of particular importance for infection prevention. The present recommendations replace the previous recommendations "tuberculosis infection control" from 2012 and take into account the current national and international recommendations and as well as new scientific findings. After a description of the infection and the transmission pathways, the necessary prevention and hygiene measures in health care facilities are comprehensively presented. Since the last revision of the recommendations on infection prevention, international recommendations and the KRINKO recommendation on ending isolation have been changed. In accordance with this, under certain conditions in the case of sensitive tuberculosis, de-isolation in health care facilities can take place after 14 days without taking the sputum findings into account. The second part of the recommendations explains in detail the measures to be taken in special situations and areas, such as general practitioners, ambulance services and care facilities. Here, the recommendations on respiratory protection have been simplified; for staff, an FFP2 mask is now generally considered sufficient.

Tuberculosis in times of war and crisis: Epidemiological trends and characteristics of patients born in Ukraine, Germany, 2022.

The Russian invasion of Ukraine in 2022 caused a large migration to other European countries, including Germany. This movement impacted the TB epidemiology, as Ukraine has a higher prevalence of TB and multidrug-resistant TB rates compared to Germany. Our descriptive analysis of TB surveillance data reveals important information to improve TB care in people displaced from Ukraine. We observed an expected increase in the number of TB patients born in Ukraine, which is, however, so far below WHO/Europe estimates.

[Tuberculosis in adulthood - The Sk2-Guideline of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the diagnosis and treatment of adult tuberculosis patients]. / Tuberkulose im Erwachsenenalter.

In Germany tuberculosis is a rare disease and usually well treatable. Worldwide it is one of the most common infectious diseases with approximately 10 million new cases every year. Even with low incidences in Germany, tuberculosis is an important differential diagnosis especially due to international developments and migration movements. With a decreasing experience there's a continuous demand on accurate and up-to-date information. This guideline covers all aspects of microbiological diagnostics, basic principles of standard therapy, treatment of extrapulmonary tuberculosis, management of side effects, special features of diagnosis and treatment of resistant tuberculosis, and treatment in TB-HIV coinfection. Also, it explains when treatment in specialized centers is required, aspects of care and legal regulations and the diagnosis and preventive therapy of latent tuberculosis infection. The update of the S2k guideline "Tuberculosis in Adults" is intended to serve as a guideline for prevention, diagnosis, and treatment of tuberculosis for all those involved in tuberculosis care and to help meet the current challenges in dealing with tuberculosis in Germany.

Pilot study to identify missed opportunities for prevention of childhood tuberculosis.

Tuberculosis (TB) in exposed children can be prevented with timely contact tracing and preventive treatment. This study aimed to identify potential barriers and delays in the prevention of childhood TB in a low-incidence country by assessing the management of children subsequently diagnosed with TB. A pilot retrospective cohort study included children (< 15 years) treated for TB between 2009 and 2016 at a tertiary care hospital in Berlin, Germany. Clinical data on cases and source cases, information on time points of the diagnostic work up, and preventive measures were collected and analyzed. Forty-eight children (median age 3 years [range 0.25-14]) were included; 36 had been identified through contact tracing, the majority (26; 72.2%) being < 5 years. TB source cases were mostly family members, often with advanced disease. Thirty children (83.3%) did not receive prophylactic or preventive treatment, as TB was already prevalent when first presented. Three cases developed TB despite preventive or prophylactic treatment; in three cases (all < 5 years), recommendations had not been followed. Once TB was diagnosed in source cases, referral, assessment, TB diagnosis, and treatment were initiated in most children in a timely manner with a median duration of 18 days (interquartile range 6-60, range 0-252) between diagnosis of source case and child contact (information available for 35/36; 97.2%). In some cases, notable delays in follow-up occurred. CONCLUSION: Prompt diagnosis of adult source cases appears to be the most important challenge for childhood TB prevention. However, improvement is also needed in the management of exposed children. WHAT IS KNOWN: • Following infection with Mycobacterium tuberculosis, young children have a high risk of progression to active and severe forms of tuberculosis (TB). • The risk of infection and disease progression can be minimized by prompt identification of TB-exposed individuals and initiation of prophylactic or preventive treatment. WHAT IS NEW: • We could show that there are avoidable time lags in diagnosis in a relevant proportion of children with known TB exposure. • Delayed diagnosis of adult source cases, losses in follow-up examinations, and delay in referral to a specialized TB clinic of TB-exposed children, especially among foreign-born children, appear to be the main issue in this German pediatric study cohort.

Targeting screening and treatment for latent tuberculosis infection towards asylum seekers from high-incidence countries - a model-based cost-effectiveness analysis.

BACKGROUND: Enhancing tuberculosis (TB) prevention and care in a post-COVID-19-pandemic phase will be essential to ensure progress towards global TB elimination. In low-burden countries, asylum seekers constitute an important high-risk group. TB frequently arises post-immigration due to the reactivation of latent TB infection (LTBI). Upon-entry screening for LTBI and TB preventive treatment (TPT) are considered worthwhile if targeted to asylum seekers from high-incidence countries who usually present with higher rates of LTBI. However, there is insufficient knowledge about optimal incidence thresholds above which introduction could be cost-effective. We aimed to estimate, among asylum seekers in Germany, the health impact and costs of upon-entry LTBI screening/TPT introduced at different thresholds of country-of-origin TB incidence. METHODS: We sampled hypothetical cohorts of 30-45 thousand asylum seekers aged 15 to 34 years expected to arrive in Germany in 2022 from cohorts of first-time applicants observed in 2017-2019. We modelled LTBI prevalence as a function of country-of-origin TB incidence fitted to data from observational studies. We then used a probabilistic decision-analytic model to estimate health-system costs and quality-adjusted life years (QALYs) under interferon gamma release assay (IGRA)-based screening for LTBI and rifampicin-based TPT (daily, 4 months). Incremental cost-effectiveness ratios (ICERs) were calculated for scenarios of introducing LTBI screening/TPT at different incidence thresholds. RESULTS: We estimated that among 15- to 34-year-old asylum seekers arriving in Germany in 2022, 17.5% (95% uncertainty interval: 14.2-21.6%) will be latently infected. Introducing LTBI screening/TPT above 250 per 100,000 country-of-origin TB incidence would gain 7.3 (2.7-14.8) QALYs at a cost of €51,000 (€18,000-€114,100) per QALY. Lowering the threshold to ≥200 would cost an incremental €53,300 (€19,100-€122,500) per additional QALY gained relative to the ≥250 threshold scenario; ICERs for the ≥150 and ≥ 100 thresholds were €55,900 (€20,200-€128,200) and €62,000 (€23,200-€142,000), respectively, using the next higher threshold as a reference, and considerably higher at thresholds below 100. CONCLUSIONS: LTBI screening and TPT among 15- to 34-year-old asylum seekers arriving in Germany could produce health benefits at reasonable additional cost (with respect to international benchmarks) if introduced at incidence thresholds ≥100. Empirical trials are needed to investigate the feasibility and effectiveness of this approach.

Completeness of tuberculosis case notifications in Germany in 2013-2017: first results of an inventory study.

BACKGROUND: Evaluating the completeness of tuberculosis (TB) notification data is important for monitoring of TB surveillance systems. We conducted an inventory study to calculate TB underreporting in Germany in 2013-2017. METHODS: Acquisition of two pseudonymized case-based data sources (national TB notification data and antibiotic resistance surveillance data) was followed by two-source Capture-recapture (CRC) analysis, as case-based data from a third source was unavailable. Aggregated data on consumption of a key anti-TB drug (pyrazinamide [PZA]) was compared to an estimated need for PZA based on TB notification data to obtain an independent underreporting estimation. Additionally, notified TB incidence was compared to TB rate in an aggregated health insurance fund dataset. RESULTS: CRC and PZA-based approaches indicated that between 93 and 97% (CRC) and between 91 and 95% (PZA) of estimated cases were captured in the national TB notification data in the years 2013-2017. Insurance fund dataset did not indicate TB underreporting on the national level in 2017. CONCLUSIONS: Our results suggest that more than 90% of estimated TB cases are captured within the German TB surveillance system, and accordingly the TB notification rate is likely a good proxy of the diagnosed TB incidence rate. An increase in underreporting and discrepancies however should be further investigated.

First-line tuberculosis drug resistance patterns and associated risk factors in Germany, 2008-2017.

BACKGROUND: Drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), poses a threat to public health. While standard surveillance focuses on Rifampicin and/or Isoniazid resistance, little is known about other resistance patterns. This study aims to identify predominant drug resistance (DR) patterns in Germany and risk factors associated with them in order to inform diagnostic and treatment strategies. METHODS: Case-based TB surveillance data notified in Germany from 2008-2017 were utilized to investigate DR and MDR-TB patterns for Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), and Streptomycin (S). Predominant patterns were further analyzed stratified by sex, age, country of birth, prior TB, and disease site. Multivariable logistic regression was conducted to determine risk factors associated with any resistance, MDR-TB, and complete HRZES resistance. RESULTS: 26,228 cases with complete DST results were included in the study, among which 3,324 cases had any DR (12.7%). Four patterns were predominant, representing about ¾ of all cases with any resistance (S: 814 [3.1%]; H: 768 [2.9%]; HS: 552 [2.1%]; Z: 412 [1.6%]). High proportions of S and H resistances were found among both German and foreign-born populations, especially those born in Eastern Europe, and were unexpectedly high among children (H: 4.3%; S: 4.6%). Foreign-born cases had significantly higher proportion of any resistance (16.0%) and MDR-TB (3.3%) compared to German-born cases (8.3% and 0.6%). Of 556 MDR-TB cases, 39.2% showed complete HRZES resistance. Logistic regression revealed having prior TB and being foreign-born as consistently strong risk factors for any DR, MDR-TB, and complete HRZES resistance. CONCLUSIONS: DR patterns observed in Germany, particularly for MDR-TB were more complex than expected, highlighting the fact that detailed drug-testing results are crucial before incorporating HRZES drugs in MDR-TB treatment. Furthermore, the relatively high rate of H-resistance in Germany provides strong rationale against the use of only H-based preventive therapy for LTBI.

Assessment of the use and need for an integrated molecular surveillance of tuberculosis: an online survey in Germany.

BACKGROUND: The implementation of an integrated molecular surveillance (IMS) of tuberculosis (TB) is of high priority for TB control. IMS is defined as the systematic inclusion of molecular typing results in the national TB surveillance system. Although not standardized, an IMS of TB is already implemented in several low TB incidence countries. Germany is in the process of implementing a nationwide IMS of TB. This requires close collaboration between national and local health authorities. We conducted an online survey to understand the current use of molecular typing results for TB surveillance among the local public health offices (PHO)s in Germany, and to collect their perception and expectations towards the implementation of a nationwide IMS of TB. METHODS: The online survey was developed using the software Voxco and included 31 questions. The survey was sent to all the 377 local PHOs in Germany in April 2017. Responses were collected until June 2017. RESULTS: A total of 174/377 (46.2%) local PHOs participated in our survey, and 88/377 (23.3%) used molecular typing results in their routine TB surveillance work. The PHOs used molecular typing results especially as support for epidemiological contact tracing (62/88, 70.4%). We found statistically significant differences between answers of PHOs that did not use molecular typing results (n = 86) vs. PHOs that did use molecular typing results (n = 88): the latter perceived the use of molecular typing results as more beneficial for their work compared to the former (65.9% vs. 34.9%, p < 0.05). Moreover, the PHOs using molecular typing results expect for the future more support and coordination from regional and national public health institutes, especially regarding the identification and analysis of molecular clusters. CONCLUSIONS: Our study is a step forward in the broader goal of implementing an IMS of TB in Germany. The local PHOs currently using the molecular typing results highlighted their positive attitude towards the implementation of an IMS, but also their needs of more support. Similar assessments might serve as an example for other countries which are on the way to implement a nationwide IMS of TB.

Find and treat or find and lose? Tuberculosis treatment outcomes among screened newly arrived asylum seekers in Germany 2002 to 2014.

BackgroundGermany has a low tuberculosis (TB) incidence. A relevant and increasing proportion of TB cases is diagnosed among asylum seekers upon screening. Aim: We aimed to assess whether cases identified by screening asylum seekers had equally successful and completely reported treatment outcomes as cases diagnosed by passive case finding and contact tracing in the general population. Methods: We analysed characteristics and treatment outcomes of pulmonary TB cases notified in Germany between 2002 and 2014, stratified by mode of case finding. We performed three multivariable analyses with different dependent variables: Model A: successful vs all other outcomes, Model B: successful vs documented non-successful clinical outcome and Model C: known outcome vs lost to follow-up. Results: TB treatment success was highest among cases identified by contact tracing (87%; 3,139/3,591), followed by passive case finding (74%; 28,804/39,019) and by screening asylum seekers (60%; 884/1,474). Cases identified by screening asylum seekers had 2.4 times higher odds of not having a successful treatment outcome as opposed to all other outcomes (A), 1.4 times higher odds of not having a successful treatment outcome as opposed to known non-successful outcomes (B) and 2.3 times higher odds of loss to follow-up (C) than cases identified by passive case finding. Conclusion: Screened asylum seekers had poorer treatment outcomes and were more often lost to follow-up. Linking patients to treatment facilities and investigating potential barriers to treatment completion are needed to secure screening benefits for asylum seekers and communities.

[Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. / S2k-Leitlinie: Tuberkulose im Erwachsenenalter.

Since 2015 a significant increase in tuberculosis cases is notified in Germany, mostly due to rising numbers of migrants connected to the recent refugee crisis. Because of the low incidence in previous years, knowledge on tuberculosis is more and more limited to specialized centers. However, lung specialist and healthcare workers of other fields have contact to an increasing number of tuberculosis patients. In this situation, guidance for the management of standard therapy and especially for uncommon situations will be essential. This new guideline on tuberculosis in adults gives recommendations on diagnosis, treatment, prevention and prophylaxis. It provides a comprehensive overview over the current knowledge, adapted to the specific situation in Germany. The German Central Committee against Tuberculosis (DZK e. V.) realized this guideline on behalf of the German Respiratory Society (DGP). A specific guideline for tuberculosis in the pediatrics field will be published separately. Compared to the former recommendations of the year 2012, microbiological diagnostics and therapeutic drug management were given own sections. Chapters about the treatment of drug-resistant tuberculosis, tuberculosis in people living with HIV and pharmacological management were extended. This revised guideline aims to be a useful tool for practitioners and other health care providers to deal with the recent challenges of tuberculosis treatment in Germany.

Contact investigation after a fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an aircraft, Germany, July 2013.

In July 2013, a passenger died of infectious extensively drug-resistant tuberculosis (XDR-TB) on board of an aircraft after a 3-hour flight from Turkey to Germany. Initial information indicated the patient had moved about the aircraft coughing blood. We thus aimed to contact and inform all persons exposed within the aircraft and to test them for newly acquired TB infection. Two-stage testing within 8 weeks from exposure and at least 8 weeks after exposure was suggested, using either interferon gamma release assays (IGRAs) or tuberculin skin test (TST). The TST cut-off was defined at a diameter > 10 mm; for differentiation between conversion and boosting, conversion was defined as increase of skin induration > 5 mm. Overall, 155 passengers and seven crew members were included in the investigation: the questionnaire response rate was 83%; 112 (69%) persons were tested at least once for TB infection. In one passenger, who sat next to the area where the patient died, a test conversion was registered. As of March 2017, no secondary active TB cases have been reported. We describe an unusual situation in which we applied contact tracing beyond existing European guidelines; we found one latent tuberculosis infection in a passenger, which we consider probably newly acquired.

Treatment outcome in children with nontuberculous mycobacterial lymphadenitis: A retrospective follow-up study.

INTRODUCTION: Information on the long-term treatment outcome following nontuberculous mycobacterial (NTM) lymphadenitis is very limited. We performed a study to (a) compare cure rates following different initial treatment courses, (b) describe subsequent treatment courses and their outcomes, and (c) determine the occurrence of late sequelae in immunocompetent children with NTM lymphadenitis. MATERIALS AND METHODS: In 2011, we conducted a retrospective follow-up study in 71 parents whose children had been hospitalized with NTM disease 2002-2005. A telephone survey was performed using a standardized questionnaire to collect information on the therapeutic management and treatment outcome. RESULTS: Of 61 children with NTM lymphadenitis, 33 (54%) children were cured after the initial treatment. We found no significant difference in cure rates following surgical intervention only (45%, 13/29 children) and a combination of surgical intervention and chemotherapy (61%, 19/31 children). In 7 out of 11 children, the cure rate following complete lymph node excision was 64%. Subsequent courses of treatment including repeated surgical intervention, combination therapy, chemotherapy only, and wait-and-see strategy in children where initial therapy failed resulted in the cure of all 61 children. In four children (7%), recurrences were observed up to 5 years later. CONCLUSIONS: Our study showed that recurrent NTM lymphadenitis might be observed several years after initial resolution of disease. The cure rate following complete lymph node excision was lower than reported in other studies. Subsequent treatment courses were necessary in half of the children. Physicians and parents need to be aware that NTM lymphadenitis in children requires careful choice of intervention and active follow-up.

A joint cross-border investigation of a cluster of multidrug-resistant tuberculosis in Austria, Romania and Germany in 2014 using classic, genotyping and whole genome sequencing methods: lessons learnt.

Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.